Genetic Alterations Associated With Interval Breast Cancer Diagnosis

Get Permission

In a Swedish study reported in JAMA Oncology, Rodriguez et al identified characteristics of interval breast cancers—those diagnosed between two screening examinations—compared with screen-detected cancers on the basis of analysis of rare germline genetic deleterious protein-truncating variants.

As noted by the investigators, interval breast cancers have worse clinicopathologic characteristics and poorer prognosis vs screen-detected cancers; the association of rare germline genetic variants with interval cancer has not been studied.

Study Details

The study involved women aged 40 to 76 years who were attending mammographic screening every 2 years in Sweden. The current analysis included a total of 4,121 patients with a diagnosis of breast cancer, including interval cancer in 1,229 and screen-detected cancer in 2,892, between January 2001 and January 2016, and a total of 5,631 age-matched controls. Germline protein-truncating variants in 34 susceptibility genes were analyzed by targeted sequencing. Patients with breast cancer were followed for survival until 2021.

Key Findings

Compared with controls, the odds ratios (ORs) for carrying protein-truncating variants of the five major breast cancer genes—ATM, BRCA1, BRCA2, CHEK2, and PALB2—were 2.62 (95% confidence interval [CI] = 2.02–3.40) among all women diagnosed with breast cancer, 2.34 (95% CI = 1.76–3.11) among those with screen-detected cancer, and 3.30 (95% CI = 2.38–4.59) among those with interval cancer.   

Protein-truncating variants of ATM, BRCA1, BRCA2, CHEK2, and PALB2 were more common in patients with interval cancer vs screen-detected cancer (OR = 1.48, 95% CI = 1.06–2.05), with the strongest association observed for BRCA1/2 and PALB2 variants (OR = 1.92, 95% CI = 1.17–3.15). These findings were also pronounced in the subset of patients with interval cancer and low mammographic density at prior screening (OR = 1.87, 95% CI = 1.22–2.85). Family history of breast cancer together with protein-truncating variants of any of the five genes was associated with an increased likelihood of diagnosis of interval cancer vs screen-detected cancer (OR = 3.95, 95% CI = 1.97–7.92).

Analysis of 10-year breast cancer–specific survival showed that among patients with a diagnosis of interval cancer, carriers of protein-truncating variants in any of the five genes had significantly worse survival vs those not carrying protein-truncating variants in any of the genes (hazard ratio = 2.04, 95% CI = 1.06–3.92).

The investigators concluded, “The results of this study may be helpful in future optimizations of screening programs that aim to lower mortality as well as the clinical treatment of patients with breast cancer.”

Juan Rodriguez, PhD, of the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the Swedish Research Council, Swedish Cancer Society, and others. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.