Circulating growth factor concentrations and breast cancer risk: a nested case-control study of IGF-1, IGFBP-3, and breast cancer in a family-based cohort

Background Insulin-like growth factor 1 (IGF-1) and binding protein 3 (IGFBP-3) are associated with breast cancer in women at average risk of cancer. Less is known whether these biomarkers also predict risk in women with breast cancer family history. Methods We conducted a nested case-control study within the New York site of the Breast Cancer Family Registry (BCFR, n = 80 cases, 156 controls), a cohort enriched for breast cancer family history. Using conditional logistic regression, we estimated the association between IGF-1 and IGFBP-3 levels and breast cancer risk and examined whether this risk differed by predicted absolute breast cancer risk based on pedigree models. Results The overall association between IGF-1 or IGFBP-3 elevation (≥ median in controls) and breast cancer risk was elevated, but not statistically significant (IGF-1 OR = 1.37, 95% CI = 0.66–2.85; IGFBP-3 OR = 1.62, 95% CI = 0.81–3.24). Women with elevated predicted absolute 10-year risk ≥ 3.4% and elevated IGFBP-3 (≥ median) had more than a 3-fold increased risk compared to women with lower predicted absolute 10-year risk (< 3.4%) and low IGFBP-3 (OR = 3.47 95% CI = 1.04–11.6). Conclusions These data offer some support that the overall magnitude of the associations between IGF-1 and IGFBP3 seen in average risk cohorts may be similar in women enriched with a strong breast cancer family history.

Personalizing Breast Cancer Screening Based on Polygenic Risk and Family History

Background We assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years. Methods Two established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age (30, 35, 40, 45, and 50 years) and interval (annual, hybrid, biennial, triennial). The benefits (breast cancer deaths averted, life-years gained) and harms (false-positive mammograms, overdiagnoses) were compared with those seen with 3 established screening guidelines. Results Women with a breast cancer family history who initiated biennial screening at age 40 years (vs 50 years) had a 36% (model range = 29%-40%) increase in life-years gained and 20% (model range = 16%-24%) more breast cancer deaths averted, but 21% (model range = 17%-23%) more overdiagnoses and 63% (model range = 62%-64%) more false positives. Screening tailored to PRS vs biennial screening from 50 to 74 years had smaller positive effects on life-years gained (20%) and breast cancer deaths averted (11%) but also smaller increases in overdiagnoses (10%) and false positives (26%). Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained (29%) and breast cancer deaths averted (18%). Conclusions Our results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected.

Generalizability of Polygenic Risk Scores for Breast Cancer in the Multiethnic eMERGE Study

Background: The majority of polygenic risk scores (PRS) for breast cancer have been developed and validated using cohorts of European ancestry (EA). Less is known about the generalizability of these PRS in other ancestral groups. Methods: The Electronic Medical Records and Genomics (eMERGE) network cohort dataset was used to evaluate the performance of seven previously developed PRS (three EA-based PRSs, and four non-EA based PRSs) in three major ancestral groups. Each PRS was separately evaluated in EA (cases: 3939; controls: 28840), African ancestry (AA) (cases: 121; controls: 1173) and self-reported LatinX ancestry (LA) (cases: 92; controls: 1363) women. We assessed the association between breast cancer risk and each PRS, adjusting forage, study site, breast cancer family history, and first three ancestry informative principal components. Results: EA-based PRSs were significantly associated with breast cancer risk in EA women per one SD increase (odds ratio [OR]=1.45, 95% confidence interval [CI]=1.40-1.51), and LA women (OR=1.41, 95% CI=1.13-1.77), but not AA women (OR=1.13, 95% CI=0.92-1.40). There was no statistically significant association for the non-EA PRSs in all ancestry groups, including an LA-based PRS and an AA-based PRS. Conclusion: We evaluated EA-derived PRS for estimating breast cancer risk using the eMERGE dataset and found they generalized well in LA women but not in AA women. For non-EA based PRSs, we did not replicate previously reported associations for the respective ancestries in the eMERGE cohort. Our results highlight the need to improve representation of diverse population groups, particularly AA women, in research cohorts.

Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women’s Environmental Cancer and Radiation Epidemiology Study

Purpose The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.