| 1. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 2. |
- Holm, Johanna, et al.
(författare)
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Associations of breast cancer risk prediction tools with tumor characteristics and metastasis
- 2016
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Ingår i: Journal of Clinical Oncology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0732-183X. ; 34:3, s. 251-U109
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The association between established risk factors for breast cancer and subtypes or prognosis of the disease is not well known. We analyzed whether the Tyrer-Cuzick–predicted 10-year breast cancer risk score (TCRS), mammographic density (MD), and a 77-single nucleotide polymorphism polygenic risk score (PRS) were associated with breast cancer tumor prognosticators and risk of distant metastasis. Patients and Methods: We used a case-only design in a population-based cohort of 5,500 Swedish patients with breast cancer. Logistic and multinomial logistic regression of outcomes, estrogen receptor (ER) status, lymph node involvement, tumor size, and grade was performed with TCRS, PRS, and percent MD as exposures. Cox proportional hazard models were used to estimate hazard ratios (HRs) of distant metastasis. Results: Women at high risk for breast cancer based on PRS and/or TCRS were significantly more likely to be diagnosed with favorable prognosticators, such as ER-positive and low-grade tumors. In contrast, PRS weighted on ER-negative disease was associated with ER-negative tumors. When stratifying by age, the associations of TCRS with favorable prognosticators were restricted to women younger than age 50. Women scoring high in both TCRS and PRS had a lower risk of distant metastasis (HR, 0.69; 95% CI, 0.49 to 0.98). MD was not associated with any of the examined prognosticators. Conclusion: Women at high risk for breast cancer based on genetic and lifestyle factors were significantly more likely to be diagnosed with breast cancers with a favorable prognosis. Better knowledge of subtype- specific risk factors could be vital for the success of prevention programs aimed at lowering mortality.
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| 3. |
- Holm, Johanna, et al.
(författare)
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Risk factors and tumor characteristics of interval cancers by mammographic density
- 2015
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Ingår i: Journal of Clinical Oncology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0732-183X. ; 33:9, s. 1030-
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare tumor characteristics and risk factors of interval breast cancers and screen-detected breast cancers, taking mammographic density into account. Patients and Methods: Women diagnosed with invasive breast cancer from 2001 to 2008 in Stockholm, Sweden, with data on tumor characteristics (n = 4,091), risk factors, and mammographic density (n = 1,957) were included. Logistic regression was used to compare interval breast cancers with screen- detected breast cancers, overall and by highest and lowest quartiles of percent mammographic density. Results: Compared with screen-detected breast cancers, interval breast cancers in nondense breasts (≤ 20% mammographic density) were significantly more likely to exhibit lymph node involvement (odds ratio [OR], 3.55; 95% CI, 1.74 to 7.13) and to be estrogen receptor negative (OR, 4.05; 95% CI, 2.24 to 7.25), human epidermal growth factor receptor 2 positive (OR, 5.17; 95% CI, 1.64 to 17.01), progesterone receptor negative (OR, 2.63; 95% CI, 1.58 to 4.38), and triple negative (OR, 5.33; 95% CI, 1.21 to 22.46). In contrast, interval breast cancers in dense breasts (> 40.9% mammographic density) were less aggressive than interval breast cancers in nondense breasts (overall difference, P = .008) and were phenotypically more similar to screen-detected breast cancers. Risk factors differentially associated with interval breast cancer relative to screen-detected breast cancer after adjusting for age and mammographic density were family history of breast cancer (OR, 1.32; 95% CI, 1.02 to 1.70), current use of hormone replacement therapy (HRT; OR, 1.84; 95% CI, 1.38 to 2.44), and body mass index more than 25 kg/m2 (OR, 0.49; 95% CI, 0.29 to 0.82). Conclusion: Interval breast cancers in women with low mammographic density have the most aggressive phenotype. The effect of HRT on interval breast cancer risk is not fully explained by mammographic density. Family history is associated with interval breast cancers, possibly indicating disparate genetic background of screen-detected breast cancers and interval breast cancers.
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| 4. |
- Mavaddat, Nasim, et al.
(författare)
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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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| 5. |
- Strand, Fredrik, et al.
(författare)
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Longitudinal fluctuation in mammographic percent density differentiates between interval and screen-detected breast cancer
- 2016
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Ingår i: International Journal of Cancer. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0020-7136 .- 1097-0215.
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Tidskriftsartikel (refereegranskat)abstract
- Interval breast cancer (IC) has a more aggressive phenotype and higher mortality than screen-detected cancer (SDC). In this case-case study, we investigated whether the size of longitudinal fluctuations in mammographic percent density (PD fluctuation) was associated with the ratio of IC versus SDC among screened women with breast cancer. The primary study population consisted of 1,414 postmenopausal breast cancer cases, and the validation population of 1,241 cases. We calculated PD fluctuation as the quadratic mean of deviations between actual PD and the long-term trend estimated by a mixed effects model. In a logistic regression model we examined the association between PD fluctuation and IC versus SDC including adjustments for PD at last screening, age at diagnosis, BMI and hormone replacement therapy. All statistical tests were two-sided. There were 385 IC and 1,029 SDC in the primary study population, with PD fluctuations of 0.44 and 0.41 respectively (p = 0.0309). After adjustments, PD fluctuation was associated with an increased ratio of IC versus SDC, with an estimated per-standard deviation odds ratio of 1.17 (95% CI = 1.03-1.33), compared to 1.19 (95% CI = 1.04-1.38) in the validation population. In screened women with breast cancer, high fluctuation in mammographic percent density was associated with an increased ratio of IC versus SDC. Whether this is entirely related to a reduced mammographic detectability or to a biological phenotype promoting faster tumor growth remains to be elucidated.
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| 6. |
- Ugalde-Morales, Emilio, et al.
(författare)
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Association between breast cancer risk and disease aggressiveness : Characterizing underlying gene expression patterns
- 2021
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 148:4, s. 884-894
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Tidskriftsartikel (refereegranskat)abstract
- The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low-risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P <.05) including Ki-67 proliferation status (P < 5 × 10−07). Our low-risk TC-Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal-like (P < 5 × 10−13), HER2-enriched subtype (P < 5 × 10−07) and worse 10-year breast cancer-specific survival (log-rank P < 5 × 10−04). Associations between low-risk TC-Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.
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| 7. |
- Ugalde-Morales, Emilio, et al.
(författare)
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Interval breast cancer is associated with interferon immune response
- 2022
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 162, s. 194-205
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aggressive nature of breast cancers detected between planned mammographic screens, so-called interval cancers, remains elusive. Here, we aim to characterise underlying molecular features of interval cancer. Methods: From 672 patients with invasive breast cancer, we analysed gene expression differences between 90 ‘true’ interval cancer cases (i.e. women with low-dense breasts defined as per cent mammographic density <25%) and 310 screen-detected tumours while accounting for PAM50 subtypes and thus overall tumour aggressiveness. We computed an interval cancer gene expression profile (IC-Gx) in a total of 2270 breast tumours (regardless of interval cancer status) and tested for association with expression-based immune subtypes in breast cancer. In addition, we investigated the contribution of inherited and somatic genetic variants in distinct features of interval cancer. Results: We identified 8331 genes nominally associated with interval cancer (P-value < 0.05, fold-change > 1.5). Gene set enrichment analysis showed immune-related pathways as key processes altered in interval cancer. Our IC-Gx, based on 47 genes with the strongest associations (false discovery rate < 0.05), was found to be associated mainly with immune subtypes involving interferon response. We isolated an interaction network of interval cancer and interferon genes for which a significant load of somatic and germline variants in class I interferon genes was observed. Conclusion: We identified novel molecular features of interval breast cancer highlighting interferon pathways as a potential target for prevention or treatment.
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| 8. |
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