TOPLINE

In a prospective study, women with invasive lobular carcinoma (ILC) carrying certain germline pathogenic variants had a fourfold higher risk for early relapse vs noncarriers.

METHODOLOGY

• Germline pathogenic variants in several genes, most notably CDH1, are strongly associated with an increased risk for ILC, but it’s unclear whether any are associated with prognosis. Improving genetic risk stratification in ILC could inform tailored surveillance and risk-reduction strategies.
• Researchers conducted a single-center, longitudinal study involving 414 women diagnosed with primary ILC (mean age, 54 years). Patient blood samples were analyzed for 113 cancer predisposition genes using next-generation sequencing.
• Patients were classified into two groups: carriers of moderate- to high-risk breast cancer variants (including ATM, BARD1, BRCA1/2, CDH1, CHEK2, NF1, FANCM, PALB2, RAD51C, RAD51D, STK11, TP53, and PTEN) and noncarriers. In addition, polygenic risk scores (PRSs) were evaluated using a single-nucleotide polymorphism array interrogating more than 850,000 markers.
• The primary outcome was breast cancer-free survival, with Cox proportional hazards regression models used to compare outcomes between groups. The median follow-up was 3.4 years.

TAKEAWAY

• Pathogenic variants were identified in 46 of 414 patients (11%), with 20 patients (4.8%) carrying variants in moderate- to high-risk genes — most frequently in BRCA2 (1.9%) and ATM (1.2%).
• Women with moderate- to high-risk pathogenic variants had significantly reduced 5-year breast cancer-free survival compared with noncarriers (62% vs 92%; hazard ratio, 3.91; P < .001).
• Among women carrying moderate- to high-risk variants, 11 (55%) had a local, regional, or distant recurrence compared with 47 (12%) noncarriers. The median recurrence-free survival was 5.8 years vs 14.5 years, respectively.
• PRS quartiles showed no association with recurrence risk, and there was no association between PRS and germline variant status — highlighting, the study authors wrote, the current limitations of such scores as prognostic tools in ILC.

IN PRACTICE

“Our findings suggest the existence of a distinct subset of ILC characterized by germline [pathogenic variants] in breast cancer predisposition genes, which may be associated with an increased risk of early locoregional or distant relapse,” the authors of the study wrote. If validated in larger cohorts, they added, the results could help individualize patient monitoring and adjuvant therapy consideration.

SOURCE

The study, led by Giovanni Corso, MD, PhD, European Institute of Oncology, Milan, Italy, was published online in JAMA Network Open.

LIMITATIONS

The number of patients carrying moderate- to high-risk pathogenic variants was relatively small, limiting the power of subgroup analyses and generalizability. The study was conducted at a single institution, and all patients were White. The polygenic models applied were not specifically developed for ILC and may not adequately reflect prognosis in this histologic subtype.

DISCLOSURES

The study was funded by the Umberto Veronesi Foundation project. Two co-authors reported financial relationships with various pharmaceutical companies outside the submitted work. Full disclosures are available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.