scholarly journals Evaluating the prognostic performance of a polygenic risk score for breast cancer risk stratification

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Maria Olsen ◽  
Krista Fischer ◽  
Patrick M. Bossuyt ◽  
Els Goetghebeur
Keyword(s):  
Breast Cancer ◽  
Cancer Incidence ◽  
Cox Regression ◽  
Breast Cancer Incidence ◽  
Independent Study ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Prognostic Performance

Abstract Background Polygenic risk scores (PRS) could potentially improve breast cancer screening recommendations. Before a PRS can be considered for implementation, it needs rigorous evaluation, using performance measures that can inform about its future clinical value. Objectives To evaluate the prognostic performance of a regression model with a previously developed, prevalence-based PRS and age as predictors for breast cancer incidence in women from the Estonian biobank (EstBB) cohort; to compare it to the performance of a model including age only. Methods We analyzed data on 30,312 women from the EstBB cohort. They entered the cohort between 2002 and 2011, were between 20 and 89 years, without a history of breast cancer, and with full 5-year follow-up by 2015. We examined PRS and other potential risk factors as possible predictors in Cox regression models for breast cancer incidence. With 10-fold cross-validation we estimated 3- and 5-year breast cancer incidence predicted by age alone and by PRS plus age, fitting models on 90% of the data. Calibration, discrimination, and reclassification were calculated on the left-out folds to express prognostic performance. Results A total of 101 (3.33‰) and 185 (6.1‰) incident breast cancers were observed within 3 and 5 years, respectively. For women in a defined screening age of 50–62 years, the ratio of observed vs PRS-age modelled 3-year incidence was 0.86 for women in the 75–85% PRS-group, 1.34 for the 85–95% PRS-group, and 1.41 for the top 5% PRS-group. For 5-year incidence, this was respectively 0.94, 1.15, and 1.08. Yet the number of breast cancer events was relatively low in each PRS-subgroup. For all women, the model’s AUC was 0.720 (95% CI: 0.675–0.765) for 3-year and 0.704 (95% CI: 0.670–0.737) for 5-year follow-up, respectively, just 0.022 and 0.023 higher than for the model with age alone. Using a 1% risk prediction threshold, the 3-year NRI for the PRS-age model was 0.09, and 0.05 for 5 years. Conclusion The model including PRS had modest incremental performance over one based on age only. A larger, independent study is needed to assess whether and how the PRS can meaningfully contribute to age, for developing more efficient screening strategies.

scholarly journals Evaluating the Prognostic Performance of a Polygenic Risk Score for Breast Cancer Risk Stratification

2020 ◽  
Author(s):  
Maria Olsen ◽  
Krista Fischer ◽  
Patrick M. Bossuyt ◽  
Els Goetghebeur
Keyword(s):  
Breast Cancer ◽  
Cancer Incidence ◽  
Cox Regression ◽  
Breast Cancer Incidence ◽  
Independent Study ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Breast Cancers ◽  
Polygenic Risk ◽  
Prognostic Performance

Abstract Background: Polygenic risk scores (PRS) could potentially improve breast cancer screening recommendations. We analyzed how well a recently developed prevalence-based breast cancer PRS (Läll et al., 2009) performs in expressing women’s future risk of incident breast cancer. Objectives: To evaluate the prognostic performance of models using PRS and age as predictors, vs age alone, for breast cancer incidence in women from the Estonian biobank (EstBB) cohort. Methods: We analyzed data on 30,312 women from the EstBB cohort. They entered the cohort between 2002 and 2011, were between 20-89 years, without history of breast cancer, and with full 5-year follow-up by 2015. We examined PRS and other potential risk factors as possible predictors in Cox regression models for breast cancer incidence. With 10-fold cross validation we estimated 3- and 5-year breast cancer incidence from age alone and PRS plus age, fitting models on 90% of the data. Calibration, discrimination, and reclassification then expressed prognostic performance on the left-out folds. Results: A total of 101 (3.33‰) and 185 (6.1‰) incident breast cancers were observed within 3 and 5 years, respectively. For women in the current Estonian screening age (50-62 years), the ratio of observed vs PRS-age modelled 3-year incidence was 0.86 for women in the 75-85% PRS-group, 1.34 for the 85-95% PRS-group, and 1.41 for the top 5% PRS-group. For 5-year incidence, this was respectively 0.94, 1.15, and 1.08. Yet, the number of breast cancer events were relatively low in each PRS-subgroup. The model’s AUC was 0.720 (95% CI: 0.675-0.765) for 3-year and 0.704 (95% CI: 0.670-0.737) for 5-year, respectively, just 0.022 and 0.023 higher than for the model with age alone. Using a 1% risk prediction threshold, the 3-year NRI for the PRS-age model was 0.09 and 0.05 for 5 years.Conclusion: The model including PRS had modest incremental performance. This suggests that the potential benefit of adding PRS to age for guiding screening likely affects a relatively small proportion of women. A larger, independent study is needed to assess whether and how the PRS can meaningfully contribute to developing more efficient screening strategies.

scholarly journals Polygenic risk, susceptibility genes, and breast cancer over the life course

2020 ◽  
Author(s):  
Nina Mars ◽  
Elisabeth Widén ◽  
Sini Kerminen ◽  
Tuomo Meretoja ◽  
Matti Pirinen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Clinical Decision Making ◽  
Breast Cancer Mortality ◽  
Breast Cancer Incidence ◽  
Positive Family History ◽  
Risk Scores ◽  
Limited Information ◽  
Polygenic Risk ◽  
Fold Enrichment

ABSTRACTPolygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their clinical applicability. We set out to study how PRS could help in clinical decision making. Among 99,969 women in the FinnGen study with 6,879 breast cancer cases, the PRS was associated not only with breast cancer incidence but also with a range of breast cancer-related endpoints. Women with a breast cancer PRS above the 90th percentile had both higher breast cancer mortality (HR 2.40, 95%CI 1.82-3.17) and higher risk for non-localized disease at diagnosis (HR 2.94, 95%CI 2.63-3.28), compared to those with PRS <80th percentile. The PRS modified the breast cancer risk of two high-impact frameshift risk variants. Women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 263 carriers) and an average PRS (20-80th percentile) had a lifetime risk of breast cancer at 58% (95%CI 50-66%), which increased to 85% (70-100%) with a high PRS (>90th percentile), and decreased to 27% (15-39%) with a low PRS (<20th percentile). Similarly, for c.1100delC in CHEK2 (3.7-fold enrichment; 1,543 carriers), the respective lifetime risks were 27% (95%CI 25-30%), 59% (52-67%), and 18% (13-22%). Among breast cancer cases, a PRS >90th percentile was associated with risk of contralateral breast cancer with HR 1.66 (95%CI 1.24-2.22). Finally, the PRS significantly refined the risk assessment of women with first-degree relatives diagnosed with breast cancer, i.e. the combination of high PRS (>90th percentile) and a positive family-history was associated with a 2.33-fold elevated risk (95%CI 1.57-3.46) compared to a positive family history alone. These findings demonstrate opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members.

scholarly journals Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study

2019 ◽  
Vol 37 (21) ◽  
pp. 1800-1809 ◽  
Author(s):  
Thomas P. Ahern ◽  
Anne Broe ◽  
Timothy L. Lash ◽  
Deirdre P. Cronin-Fenton ◽  
Sinna Pilgaard Ulrichsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Incidence ◽  
Dibutyl Phthalate ◽  
Cox Regression ◽  
Breast Cancer Incidence ◽  
Drug Products ◽  
Phthalate Exposure ◽  
Long Term Treatment ◽  
High Level

PURPOSE Phthalate exposure is ubiquitous and especially high among users of drug products formulated with phthalates. Some phthalates mimic estradiol and may promote breast cancer. Existing epidemiologic studies on this topic are small, mostly not prospective, and have given inconsistent results. We estimated associations between longitudinal phthalate exposures and breast cancer risk in a Danish nationwide cohort, using redeemed prescriptions for phthalate-containing drug products to measure exposure. METHODS We ascertained the phthalate content of drugs marketed in Denmark using an internal Danish Medicines Agency ingredient database. We enrolled a Danish nationwide cohort of 1.12 million women at risk for a first cancer diagnosis on January 1, 2005. By combining drug ingredient data with the Danish National Prescription registry, we characterized annual, cumulative phthalate exposure through redeemed prescriptions. We then fit multivariable Cox regression models to estimate associations between phthalate exposures and incident invasive breast carcinoma according to tumor estrogen receptor status. RESULTS Over 9.99 million woman-years of follow-up, most phthalate exposures were not associated with breast cancer incidence. High-level dibutyl phthalate exposure (≥ 10,000 cumulative mg) was associated with an approximately two-fold increase in the rate of estrogen receptor–positive breast cancer (hazard ratio, 1.9; 95% CI, 1.1 to 3.5), consistent with in vitro evidence for an estrogenic effect of this compound. Lower levels of dibutyl phthalate exposure were not associated with breast cancer incidence. CONCLUSION Our results suggest that women should avoid high-level exposure to dibutyl phthalate, such as through long-term treatment with pharmaceuticals formulated with dibutyl phthalate.

scholarly journals Risk-Reducing Salpingo-Oophorectomy and Breast Cancer Risk Reduction in the Gynecologic Oncology Group Protocol-0199 (GOG-0199)

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Phuong L Mai ◽  
Austin Miller ◽  
Mitchell H Gail ◽  
Steven Skates ◽  
Karen Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Incidence ◽  
Breast Cancer Incidence ◽  
Incidence Rates ◽  
Pathogenic Variant ◽  
Risk Reducing ◽  
Cancer Risk Reduction

Abstract Background Risk-reducing salpingo-oophorectomy (RRSO) has been associated with approximately 50% breast cancer risk reduction among women with a pathogenic variant in BRCA1 or BRCA2 (BRCA1/2), a finding that has recently been questioned. Methods We estimated incidence rates of breast cancer and all cancers combined during 5 years of follow-up among participants selecting RRSO or ovarian cancer screening (OCS) among women with a BRCA1/2 pathogenic variant or strong breast and/or ovarian cancer family history. Ovarian or fallopian tube or peritoneal cancer incidence rates were estimated for the OCS group. Breast cancer hazard ratios (HRs) for time-dependent RRSO were estimated using Cox regression with age time-scale (4943 and 4990 women-years in RRSO and OCS cohorts, respectively). All statistical tests were two-sided. Results The RRSO cohort included 925 participants, and 1453 participants were in the OCS cohort (381 underwent RRSO during follow-up), with 88 incident breast cancers diagnosed. Among BRCA1/2 pathogenic variant carriers, a non-statistically significant lower breast cancer incidence was observed in the RRSO compared with the OCS cohort (HR = 0.86, 95% confidence interval  = 0.45 to 1.67; P = .67). No difference was observed in the overall population or among subgroups stratified by prior breast cancer history or menopausal status. Seven fallopian tube and four ovarian cancers were prospectively diagnosed in the OCS cohort, and one primary peritoneal carcinoma occurred in the RRSO cohort. Conclusions These data suggest that RRSO might be associated with reduced breast cancer incidence among women with a BRCA1/2 pathogenic variant, although the effect, if present, is small. This evolving evidence warrants a thorough discussion regarding the impact of RRSO on breast cancer risk with women considering this intervention.

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