Study Identifies Genetic Variant Associated With Increased Risk of Invasive Lobular Breast Cancer
There may be significant genomic differences between patients with invasive lobular breast cancer and those with invasive ductal breast cancer, according to the results of a study presented by Sawyer et al in PLOS Genetics. This finding may lead to further insights into the biology of lobular breast tumors and, ultimately, improved outcomes.
Invasive lobular breast cancer accounts for 10% to 15% of all invasive breast carcinomas. These tumors are generally estrogen receptor–positive and have shown an association with the use of hormone replacement therapy. Although various recent trials have focused on genetic predispositions to breast cancer in general, none have examined this aspect in relationship to invasive lobular breast cancer.
Thus, the investigators undertook a study to identify nucleotide polymorphisms that may be specific to this morphologic variant. They also analyzed loci that may be associated with lobular carcinoma in situ.
Study Details and Results
The investigators analyzed the medical records of 6,023 women with lobular breast cancer, of whom 5,622 had invasive lobular breast cancer and 401 had lobular carcinoma in situ. Patient records were obtained from GLACIER (Genetics of Lobular Carcinoma in Situ in Europe), a UK study of lobular breast cancer, and the Breast Cancer Association Consortium.
Analyses of patient records were based upon the correlation between nucleotide polymorphisms and particular known breast cancer predisposition loci. Six uncorrelated nucleotide polymorphisms (rs11977670, rs2121783, rs2747652, rs3909680, rs9948182, and rs7034265) were identified and analyzed. One nucleotide polymorphism, rs11977670, reached genome-wide significance (odds ratio = 1.13; 95% confidence interval [CI] = 1.09–1.18; P = 6.0 × 10−10). None of the other five nucleotide polymorphisms were associated with lobular breast cancer at a genome-wide significance level. Of the 71 known breast cancer polymorphisms that were genotyped, 56 were associated with invasive lobular breast cancer and 15 were associated with lobular breast cancer in situ.
The investigators also attempted to assess the expression of nine genes that closely correlated with rs11977670 via breast cancer subtype (estrogen receptor–positive invasive lobular breast cancer, estrogen receptor–positive invasive ductal carcinoma, and estrogen receptor–negative invasive ductal carcinoma). Although there were no significant differences noted among the nine genes assessed in the three subtypes, three genes were associated with differential expression (BRAF, NDUFB2, and SLC37A3). Incidentally, two genes did show a difference between estrogen receptor–positive and estrogen receptor–negative cancers, but this finding was not related to lobular-specific breast cancer.
Significant Differences in Lobular and Ductal Breast Cancer
From the data analyzed through all phases of this study, the strongest associations of nucleotide polymorphisms with genotypes were found to be rs2981579 with FGFR2 and rs3803662 with TOX3. Only one of the seven estrogen receptor–negative specific loci (rs12710696) showed a significant association with invasive lobular carcinoma.
After completion of the analytic comparison between nucleotide polymorphisms and genotypes, it was found that there was no significant heterogeneity between invasive lobular breast cancer and invasive lobular breast cancer in situ. However, there were significant differences between patients with invasive lobular breast cancer and those with invasive ductal breast cancer.
Clinical Implications
These findings showed that via identification of specific nucleotide polymorphisms, clinicians may be better able to target genes that are associated with invasive lobular breast cancer. This study should stir continued research that can determine which genes are regulated by key nucleotide polymorphisms. As for invasive lobular breast cancer in situ, the results of this study affirmed that many of the specific nucleotide polymorphisms that predispose to invasive lobular breast cancer also predispose to invasive lobular breast cancer in situ.
The investigators remarked, “Overall, our analyses show that genetic predisposition to invasive ductal carcinoma and lobular lesions (both invasive lobular carcinoma and invasive lobular carcinoma in situ) overlaps to a large extent, but there are important differences that are likely to provide insights into the biology of lobular breast tumors.”
Elinor Sawyer, MD, of the Division of Cancer Studies, Kings College London, Guy’s Hospital, London, is the corresponding author of the article in PLOS Genetics.
Funding for this study came from the National Institute for Health Research (NIHR) Biomedical Research Centre. The authors reported no potential conflicts of interest.
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