Immunohistochemical detection of Claudin low breast cancer; which subcellular level to be assessed?

Objectives: Claudin low breast cancers are often high grade, triple negative tumours with poor prognosis.  They are identified at genetic level and are not diagnosed routinely by immunohistochemistry. The objective was to determine the best subcellular level to detect Claudin low breast cancer by immunohistochemistry, in terms of their histopathological prognostic features.Methods: This cross sectional study included all archival breast cancer tissue collected up to December 2015 in our unit. Tissue microarrays (TMA) were constructed using 23 breast cancer cores with a diameter of 2mm, in each TMA. TMAs were immunohistochemically stained for Claudin 3 expression and was scored as; no staining=0, weak staining=1, moderate staining=2 and strong staining=3, separately for membrane, cytoplasmic and nuclear staining. A score <2 was considered Claudin low and analysed against the histopathological prognostic features of the breast cancer.Results: A total of 546 breast cancers were assessed. Claudin low expression was identified at cytoplasmic, membrane and nuclear level in 74.9%, 74.5% and 42% of breast cancers respectively. Low nuclear expression of Claudin 3 was associated with high grade (p=0.028), Nottingham Prognostic Index of >3.4 (p=0.028), ER and PR negative (p<0.001) and HER 2 negative (p=0.013) tumours while low membrane staining was associated with low grade (p=0.038), HER 2 negative (p<0.001) breast cancers. Low cytoplasmic staining was associated with HER 2 negative breast cancer only (p=0.002).Conclusions: Nuclear staining for Claudin should be assessed to identify Claudin low breast cancer by immunohistochemistry as it significantly associates with most of the Claudin low breast cancer characteristics

Clinico-pathological factors influencing the recurrence free interval of patients with recurrent breast cancer

Objectives: Clinico-pathological factors affect the prognosis of breast cancer (BC) reflecting the heterogeneity of the disease. Following initial treatment, there is an ongoing risk of recurrence. The influence of these prognostic factors on the time taken to develop recurrence is not well established. This study was designed to determine the effect of clinic-pathological factors on the recurrence free interval (RFI) of BC patients with recurrent disease.Methods: This retrospective study included BC patients who had sought the immunohistochemistry laboratory services of our unit from May 2006 to December 2012. Mean follow up time was 45±23 months. All BC patients who had recurrences (loco-regional and distant metastasis) during the follow up period were enrolled. RFI was measured from the date of first therapeutic intervention to the date of confirmation of recurrence. Chi-square test was used for analysis.Results: Out of 944 BC patients, 188(mean age 50±11 years), had recurrences (loco-regional =35, distant metastasis =153). More than 50% of them had recurrence within 24 months of initial treatment (local=18/35 and distant=81/153). Mean RFI was 33±21 months for oestrogen receptor (ER)/progesterone receptor (PR) positive BC and 22±16 months for ER/PR negative BC. ER/PR positive BCs had a significant upward trend in developing recurrences over time (χ2 trend<0.001) while the rest had a downward trend. Other clinico-pathological factors were not associated with RFI. Majority (49/53) of the ER/PR positive BC patients had received hormone therapy and 179/188 BC patients had received chemotherapy.Conclusions: ER/PR positive BC patients develop late recurrences while hormone receptor negative patients develop early recurrences depicting late and early treatment failure in respective groups

Practical implications of gene-expression-based assays for breast oncologists

Gene-expression profiling has had a considerable impact on our understanding of breast cancer biology, and more recently on clinical care. Two statistical approaches underlie these advancements. Supervised analyses have led to the development of gene-expression signatures designed to predict survival and/or treatment response, which has resulted in the development of new clinical assays. Unsupervised analyses have identified numerous biological signatures including signatures of cell type of origin, signaling pathways, and of cellular proliferation. Included within these biological signatures are the molecular subtypes known as the ‘intrinsic’ subtypes of breast cancer. This classification has expanded our appreciation of the heterogeneity of breast cancer and has provided a way to sub-classify the disease in a manner that might have clinical utility. In this Review, we discuss the clinical utility of gene-expression-based assays and their technical potential as clinical tools vis-a-vis the performance of breast cancer biomarkers that are the current standard of care