Abstract 32: Lynch syndrome-associated breast cancers: Clinicopathological characteristics of a case series from the Colon CFR
Authors: Rosty Christophe , Walsh Michael , Cummings Margaret , Buchanan Daniel , Arnold Sven , McKeone Diane , Walters Rhiannon , Hopper John , Jenkins Mark , Spurdle Amanda , McGuckin Michael , Lakhani Sunil , Young Joanne 
Published: February 2011

Background: Lynch Syndrome is an autosomal dominant condition which predisposes to early-onset cancer of the colorectum, endometrium, and to a lesser extent, stomach, ureter and renal pelvis, ovary, brain and small bowel. It is thought, however, that there is no significant increase in risk of developing breast cancer. The aim of this study was to determine the prevalence and clinicopathological features of breast cancers arising in families with a history of both colorectal and breast malignancy.

Design: 107 cases of breast carcinoma (BC) from 90 families were identified from the Australasian Colorectal Cancer Family Registry. Comprehensive cancer histories were available for all families: 53 (59%) families met the modified Amsterdam criteria, and the remainder had multiple cancers including at least one early onset (&lt;50 years) colorectal cancer per family. A full histology review of the breast cancers was performed by a single pathologist (MC). DNA was extracted from paraffin-embedded tumors. Tumor sections were stained for the four DNA mismatch repair (MMR) proteins MLH1, PMS2, MSH2 and MSH6. A subset of MLH1 negative tumors was assessed for MLH1 promoter methylation using a MethyLight assay. Microsatellite instability (MSI) testing was performed using a panel of 10 markers and PCR was also performed to detect the somatic V600E BRAF mutation. Results were analysed using 2×2 contingency tables and exact probabilities.

Results: Loss of one or more MMR proteins was seen in 18/107 tumors (17%): five cancers showed loss of MLH1 and PMS2, twelve tumors MSH2 and MSH6, and one tumor MSH6 alone. IHC and MSI results were concordant in 85/89 (96%) tumors tested. Invasive MMR-deficient BCs were more likely to be poorly differentiated (p=0.005), steroid hormone receptor negative (p&lt;0.05), have confluent necrosis (p=0.002), have growth in solid sheets (p&lt;0.001) and high mitotic index (p=0.002). Additionally, MMR deficient breast cancers were less likely to have contiguous in situ carcinoma present (p=0.004). No association was seen between MMR status and tumor size, lymphovascular invasion, node status, prominent eosinophilic nucleoli, or tumoral calcification. No somatic BRAF V600E mutation was found.

Conclusion: DNA mismatch repair protein deficiency was identified in 18/107 cases (17%) of breast cancer arising in a familial setting of colorectal and breast carcinoma. The MMR-deficient BCs were more likely to be high grade, steroid hormone receptor negative, have areas of solid growth, confluent necrosis and high mitotic index than MMR-proficient tumors. The study suggests that breast cancer arising in a setting of Lynch syndrome commonly demonstrates evidence of MMR deficiency and that breast cancers may represent a valid tissue option for the detection of MMR deficiency where colorectal or other spectrum tumors are difficult to obtain.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 32.