PURPOSE A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the... Show morePURPOSE A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer.METHODS Women with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment.RESULTS The PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent.CONCLUSION An increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs. (c) 2023 by American Society of Clinical Oncology Show less
Objective: To investigate the effects of different types of surgery on breast cancer prognosis in germline BRCA1/BRCA2 mutation carriers compared with noncarriers.Summary of Background Data:... Show moreObjective: To investigate the effects of different types of surgery on breast cancer prognosis in germline BRCA1/BRCA2 mutation carriers compared with noncarriers.Summary of Background Data: Although breast-conserving therapy (breast-conserving surgery followed by radiotherapy) has been associated with more local recurrences than mastectomy, no differences in overall survival have been found in randomized trials performed in the general breast cancer population. Whether breast-conservation can be safely offered to BRCA1/2 mutation carriers is debatable.Methods: The study comprised a cohort of women with invasive breast cancer diagnosed <50 years and treated between 1970 and 2003 in 10 Dutch centers. Germline DNA for BRCA1/2 testing of most-prevalent mutations covering similar to 61%) was mainly derived from paraffin-blocks. Survival analyses were performed taking into account competing risks.Results: In noncarriers (N = 5820), as well as in BRCA1 (N = 191) and BRCA2 (N = 70) mutation carriers, approximately half of the patients received breast-conserving therapy. Patients receiving mastectomy followed by radiotherapy had prognostically worse tumor characteristics and more often received systemic therapy. After adjustment for these potential confounders, patients who received breast-conserving therapy had a similar overall survival compared with patients who received mastectomy, both in noncarriers (hazard ratio [HR] = 0.95, confidence interval [CI] = 0.85-1.07, P = 0.41) and BRCA1 mutation carriers (HR = 0.80, CI = 0.42-1.51, P = 0.50). Numbers for BRCA2 were insufficient to draw conclusions. The rate of local recurrences after breast-conserving therapy did not differ between BRCA1 carriers (10-year risk = 7.3%) and noncarriers (10-year risk = 7.9%).Conclusion: Our results, together with the available literature, provide reassurance that breast-conserving therapy is a safe local treatment option to offer to BRCA1 mutation carriers with invasive breast cancer. Show less
Broek, A.J. van den; Ruiter, K. de; van't Veer, L.J.; Tollenaar, R.A.E.M.; Leeuwen, F.E. van; Verhoef, S.; Schmidt, M.K. 2015
Background: Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site... Show moreBackground: Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases. Methods: Array Comparative Genomic Hybridization (aCGH) was employed to asses DNA copy number changes in primary colorectal tumors of three distinctive patient groups. This included formalin-fixed, paraffin-embedded tissue of patients who developed liver metastases (LM; n = 36), metastases (PM; n = 37) and a group that remained metastases-free (M0; n = 25). A novel statistical method for identifying recurrent copy number changes, KC-SMART, was used to find specific locations of genomic aberrations specific for various groups. We created a classifier for organ specific metastases based on the aCGH data using Prediction Analysis for Microarrays (PAM). Results: Specifically in the tumors of primary CRC patients who subsequently developed liver metastasis, KC-SMART analysis identified genomic aberrations on chromosome 20q. LM-PAM, a shrunken centroids classifier for liver metastases occurrence, was able to distinguish the LM group from the other groups (M0&PM) with 80% accuracy (78% sensitivity and 86% specificity). The classification is predominantly based on chromosome 20q aberrations. Conclusion: Liver specific CRC metastases may be predicted with a high accuracy based on specific genomic aberrations in the primary CRC tumor. The ability to predict the site of metastases is important for improvement of personalized patient management. Show less
Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations.... Show moreBackground Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria are in use to decide which patients qualify for TP53 mutation analysis, including the LFS, Li-Fraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest mutation detection rate and sensitivity in Dutch families. We describe the tumour spectrum in TP53-positive families and calculated tumour type specific relative risks. Method A total of 180 Dutch families referred for TP53 mutation analysis were evaluated. Tumour phenotypes were verified by pathology reports or clinical records. Results A TP53 germline mutation was identified in 24 families. When the Chompret criteria were used 22/24 mutations were detected (sensitivity 92%, mutation detection rate 21%). In LFS and LFL families 18/24 mutations were found (sensitivity 75%). The two mutations detected outside the 'Chompret group' were found in a child with rhabdomyosarcoma and a young woman with breast cancer. In the mutation carriers, in addition to the classical LFS tumour types, colon and pancreatic cancer were also found significantly more often than in the general population. Conclusion We suggest TP53 mutation testing for all families fulfilling the Chompret criteria. In addition, TP53 mutation testing can be considered in the event of childhood sarcoma and breast cancer before 30 years. In addition to the risk for established LFS tumour types, TP53-positive individuals may also have an elevated risk for pancreatic and colon cancer. Show less
BRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity... Show moreBRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity is one of the few modifiable risk factors, it may provide a target to add to breast cancer prevention in this high-risk population. We examined the association between self-reported lifetime sports activity and breast cancer risk in a nationwide retrospective cohort study, including 725 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. We found a nonsignificantly decreased risk for ever engaging in sports activity (HR = 0.84, 95%CI = 0.57-1.24). Among women who had participated in sports, a medium versus low level of intensity and duration (i.e., between 11.0 and 22.7 mean MET hours/week averaged over a lifetime) reduced the risk of breast cancer (HR = 0.59, 95%CI = 0.36-0.95); no dose-response trend was observed. For mean hours/week of sports activity, a nonsignificant trend was observed (HRlow versus never = 0.93, 95%CI = 0.60-1.43; HRmedium versus never = 0.81, 95%CI = 0.51-1.29; HRhigh versus never = 0.78, 95%CI = 0.48-1.29; p (trend overall) = 0.272; p (trend active women) = 0.487). For number of years of sports activity no significant associations were found. Among women active in sports before age 30, mean MET hours/week showed the strongest inverse association of all activity measures (HRmedium versus low = 0.60, 95%CI = 0.38-0.96; HRhigh versus low = 0.58, 95%CI = 0.35-0.94; p (trend) = 0.053). Engaging in sports activity after age 30 was also inversely associated with breast cancer risk (HR = 0.63, 95%CI = 0.44-0.91). Our results indicate that sports activity may reduce the risk of breast cancer in BRCA1/2 mutation carriers. Show less
