BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

Objective: Oncotype DxTM (ODx) is a gene expression profile test that is rapidly gaining popularity for its ability to stratify breast cancer patients according to risk of distant recurrence and suggest the potential benefit of adjuvant chemotherapy (CTx). Presently, National Comprehensive Cancer Network (NCCN) guidelines suggest use of ODx for all patients with node negative (or micrometastatic node positive disease), hormone receptor positive breast cancer with a primary tumor measuring over 5mm. However, if risk factors predictive of a high recurrence score (RS) were defined, clinicians would be better able to tailor use of ODx. This study was undertaken to identify standard clinicopathologic factors that correlate with a high RS by ODx, and to determine whether these factors or RS most influenced receipt of CTx. We also measured compliance with NCCN guidelines regarding ODx utilization. Methods and Materials: We performed an IRB approved retrospective review of women with invasive breast cancer treated at Yale Cancer Center from 2008-2012 to identify patients that received ODx testing, and abstracted clinical and tumor characteristics including: age, tumor size, grade, histology, lymphovascular invasion (LVI), number of involved nodes, size of nodal metastasis, presence of extracapsular extension, hormone receptor status (including percent positive), HER2 status (by FISH), RS, and receipt of CTx. The RS was categorized into low (<18), intermediate (18-30), and high score (>30). We assessed the association between these characteristics and both high RS as well as CTx receipt using Chi squared tests and Wilcoxon ranked test as appropriate. Characteristics with a p-value <0.1 in bivariate analysis were included in logistic models to estimate the odds of a high RS and receiving CTx. Results: We identified 432 women with a median age of 58 years. RS was low, intermediate, and high in 56%, 37%, and 7%, respectively. Median tumor size was 1.6cm (range 0.1-13.2). Differentiation was rated as well, moderate, or poor in 32%, 60%, and 8%, respectively. Tumors were hormone receptor positive in 99%. ODx was used outside of NCCN guidelines in 12%. CTx was given to 30% of patients. Younger age, HER2-positivity, LVI, poor differentiation, progesterone receptor positivity (PR+) 50% or less, and RS were associated with receipt of CTx (p< = 0.01) in bivariate analyses. High RS remained independently associated with CTx receipt in multivariate analysis. Poor differentiation, PR+ 50% or less, and HER2-positivity were significantly associated with a high RS (p<0.01), and all remained independently associated with high RS in multivariate analysis. Patients with any one of these three factors had 18% odds of a high RS, versus just 1% among those without such risk factors. Conclusions: High RS independently influences recommendations for chemotherapy. Poor differentiation, PR+ 50% or less, and HER2-positivity were associated with a high RS. In the absence of any of these three factors, the likelihood of a high RS is minimal. Noncompliance with NCCN guidelines was observed. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-22.