Invasive lobular and ductal breast cancers: a systematic review and metanalysis in association with BRCA1/2 mutation status

Clinical Snapshot

Key Findings

• P Value: Difference between BRCA1 and BRCA2 associations: p<0.001

• Effect Size: BRCA1: SOR=0.32; BRCA2: SOR=1.28 (all studies), SOR=2.56 (low-bias studies)

• Primary Outcome: BRCA1 mutations significantly less frequent in ILC vs IDC; BRCA2 association varies by study quality

• Nnt Or Sensitivity: 68% reduction in BRCA1 mutation odds for ILC vs IDC; 2.56-fold increased BRCA2 odds in quality studies

• Confidence Interval: BRCA1: 95%CI (0.16-0.65); BRCA2: 95%CI (0.95-1.72) overall, (1.15-5.7) low-bias studies

Clinical Application

Highly feasible - informs existing genetic testing protocols and counselling practices Relevant to Australian practice; aligns with Cancer Australia guidelines for hereditary breast cancer and Medicare-funded genetic testing criteria Women with invasive breast cancer undergoing genetic counselling and BRCA testing

Abstract

BACKGROUND: Invasive lobular breast carcinoma (ILC) differs from invasive ductal breast carcinoma (IDC) with respect to genetic alterations and risk factors. We aimed to quantify differences in the prevalence of germline BRCA1/2 mutations between these two patients' populations. MATERIALS AND METHODS: We conducted a systematic literature search to extract data on the association between BRCA1/2 mutation status and breast cancer (BC) histological subtype (ILC and IDC). Summary odds ratios (SOR) and 95% CI were calculated using random effects univariate and bivariate models and between-study heterogeneity investigated through meta-regression and subgroup analyses. RESULTS: Twelve studies, published between 1998 and 2025, were considered, including 8004 BC women. BRCA1 mutations were significantly less frequent in patients with ILC than IDC (SOR=0.32, 95%CI (0.16-0.65)) whereas no association was found overall for BRCA2 (SOR=1.28, 95%CI (0.95-1.72)). The difference between the association with BRCA1 and BRCA2 was statistically significant (p-value<0.001). There was no indication of publication bias in BRCA1 (Egger's and Begg's test p-value=0.23, 0.12). The between study heterogeneity was 29% in BRCA1 and 0% in BRCA2. Excluding papers with high risk of bias, BRCA2 mutations were more frequent in patients with ILC than in IDC (SOR=2.56, 95%CI (1.15-5.7)). This association was primarily driven by the bivariate random-effects model, which accounts for the correlation between BRCA1 and BRCA2 estimates. CONCLUSIONS: In studies with lower risk of bias, germline BRCA2 mutations were more frequent in patients with ILC than IDC. Conversely, BRCA1 mutations are more frequently observed in IDC, particularly among younger patients and those with a positive family history of BC.

References

1. 1.Corso, G., Andreon, C., La Vecchia, C., Bottazzoli, E. I., Abruzzese, G., Favilla, K., Citterio, O., Spoldi, E., Di Silvestre, S., De Scalzi, A. M., Polizzi, A., Meduri, E., Trapani, D., Nicosia, L., Pesapane, F., Bossi, D., Brogi, E., Shen, S., Mukhtar, R., Criscitiello, C., Veronesi, P., Gandini, S., Magnoni, F., & Curigliano, G. (2026). Invasive lobular and ductal breast cancers: a systematic review and metanalysis in association with BRCA1/2 mutation status. European Journal of Cancer, 116692. https://doi.org/10.1016/j.ejca.2026.116692