Morphological predictors of BRCA1 germline mutations in young women with breast cancer

Abstract

Background:Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.Methods:We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation.Results:The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6–47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7–25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3–5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83–0.90).Conclusion:Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.

Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predictingBRCA1/2mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium

“…Additional improvements in the models’ predictive ability would be expected as information on other tumour characteristics becomes available and are incorporated into risk prediction models. For instance, tumours arising in BRCA1 and BRCA2 mutation carriers have been shown to differ from each other and from sporadic cancers in their histopathological appearance, cytological and architectural features and tumour morphology characteristics 36 37. Future model extensions should aim to incorporate such predictors.…”

Tumour morphology predicts PALB2 germline mutation status

“…The Australian BCFR probands diagnosed at ages 40 or older ( n =793) were genotyped for PALB2 c.3113G>A using Taqman assay (Southey et al , 2010). First, primary invasive breast tumours from 836 (56%) of these probands were retrieved from diagnostic centres and systematically reviewed by pathologists as described below and elsewhere (John et al , 2004; Southey et al , 2011; Dite et al , 2012). Among the breast tumours that were reviewed, 40 (5%) were from BRCA1 mutation carriers, 18 (2%) were from BRCA2 mutation carriers, 1 (0.1%) was from a carrier of ATM c.7271T>G and 4 (0.5%) were from TP53 mutation carriers (Southey et al , 1999; Andrulis et al , 2002; Chenevix-Trench et al , 2002; Apicella et al , 2003; Dite et al , 2003; Bernstein et al , 2006; Smith et al , 2007; Neuhausen et al , 2009; Mouchawar et al , 2010; Dite et al , 2012).…”

“…Characterisation of the morphology of breast cancers arising in PALB2 mutation carriers and non-carriers offers the possibility of identifying tumour morphological features predictive of an underlying germline PALB2 mutation, as they have been shown for underlying BRCA1 mutations (Lakhani et al , 1998; Southey et al , 2011; Hopper et al , 2012). This could be conducted at the time of diagnosis and therefore, be used to facilitate personalised treatment strategies, as well as enabling identification of those relatives who have also inherited a similar high breast cancer risk.…”

“…Lack of oestrogen receptor (ER) and progesterone receptor (PR) expression has also been reported to improve prediction of BRCA1 mutation status based on family history (Lakhani et al , 2002; James et al , 2006; Mavaddat et al , 2010). Using a population-based sample of 452 young women with breast cancer, we found that just two breast tumour morphological features (trabecular growth pattern and high mitotic index) were sufficient to identify 28 of the 29 BRCA1 mutation carriers in the study (Southey et al , 2011). Moreover, prediction of mutation status using these two features was more sensitive and specific than using family history alone, and when combined, the area under the receiver operator curve was in excess of 0.9.…”

Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

“…Tumors arising in BRCA1 and BRCA2 mutation carriers display characteristic pathological features (1-3). Cancers occurring among BRCA1 carriers are more frequently classified as medullary (1, 4, 5) and exhibit higher grade and mitotic count than sporadic controls (2, 6-8).…”