Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma.

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73-0.93, p < 0.001). The median frequency of CDH1/E-cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56-72%) and 73% in set B (IQR: 65-75%, p < 0.001). Cases with variable subtype calls included E-cadherin-positive ILCs harboring CDH1 missense mutations, and E-cadherin-negative ILCs with tubular elements and focal P-cadherin expression. ILCs with trabecular growth pattern were often misclassified as non-lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre-defined reference standard, if assessment is supported by E-cadherin IHC. CDH1 missense mutations associated with preserved E-cadherin protein expression, E- to P-cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.

Comparison of six breast cancer classifiers using qPCR.

MOTIVATION: Several gene expression-based risk scores and subtype classifiers for breast cancer were developed to distinguish high- and low-risk patients. Evaluating the performance of these classifiers helps to decide which classifiers should be used in clinical practice for personal therapeutic recommendations. So far, studies that compared multiple classifiers in large independent patient cohorts mostly used microarray measurements. qPCR-based classifiers were not included in the comparison or had to be adapted to the different experimental platforms. RESULTS: We used a prospective study of 726 early breast cancer patients from seven certified German breast cancer centers. Patients were treated according to national guidelines and the expressions of 94 selected genes were measured by the mid-throughput qPCR platform Fluidigm. Clinical and pathological data including outcome over five years is available. Using these data, we could compare the performance of six classifiers (scmgene and research versions of PAM50, ROR-S, recurrence score, EndoPredict and GGI). Similar to other studies, we found a similar or even higher concordance between most of the classifiers and most were also able to differentiate high- and low-risk patients. The classifiers that were originally developed for microarray data still performed similarly using the Fluidigm data. Therefore, Fluidigm can be used to measure the gene expressions needed by several classifiers for a large cohort with little effort. In addition, we provide an interactive report of the results, which enables a transparent, in-depth comparison of classifiers and their prediction of individual patients. AVAILABILITY AND IMPLEMENTATION: https://services.bio.ifi.lmu.de/pia/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Survival of breast cancer patients in rural Ethiopia.

PURPOSE: To describe the histopathological characteristics and survival of female breast cancer (BC) patients in a rural setting with limited access to adjuvant treatment. METHODS: A prospective study of 107 histologically confirmed BC patients treated with surgery from 2010 to 2016 from rural parts of western Ethiopia. Referral pathology was performed, and active follow-up was conducted. Adjusted cox regression analysis (hazard ratio [HR]) was performed. RESULTS: The median age at diagnosis was 45 (16-83) years; 57% of the patients presented with cT3/4 tumors, 71% with clinically positive lymph nodes, 21% with HER2-overexpression (Dako3+) and 68% with grade 3 tumors. Estrogen and/or progesterone receptor expressions were present in 66% and triple-negative disease in 25%. The estimated 1- and 2-year overall survival probability rates were 78 and 53%, respectively. The 2-year survival for patients with clinically positive lymph nodes was 44% compared to 73% for patients with lymph node-negative disease (HR 2.44; 95% confidence interval [95% CI] 1.19-5.02). The corresponding 2-year survival for patients with cT4 tumors was 25% versus 68% for patients with cT1-2 tumors (cT1-3 vs. cT4 HR 3.86; 95% CI 1.82-13.63). The 2-year survival for patients with hormone receptor-negative disease was 40% compared to 59% for patients with hormone receptor-positive disease (HR 1.92; 95% CI 1.06-3.47). CONCLUSION: The majority of breast cancer patients treated with surgery in rural parts of western Ethiopia are diagnosed at advanced stage and have hormone receptor-positive disease. Nearly half of the patients die within 2 years. These findings underscore the need for provision of adjuvant hormonal therapy and for the establishment of pathology service including hormone receptor testing.