Purpose
Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a ...cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients.
Methods
Swedish breast cancer patients (
n
= 699) operated 2006–2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity.
Results
Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation.
Conclusion
Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.
Gene signatures and Ki67 stratify the same breast tumor into opposing good/poor prognosis groups in approximately 20% of patients. Given this discrepancy, we hypothesized that the combination of a ...clinically relevant signature and IHC markers may provide more prognostic information than either classifier alone.
We assessed Ki67 alone or combined with ER, PR and HER2 (forming IHC subtypes), and the research versions of the Genomic Grade Index, 70-gene, cell-cycle score, recurrence score (RS), and PAM50 signatures on matching TMA/whole tumor sections and microarray data in two Swedish breast cancer cohorts of 379 and 209 patients, with median follow-up of 12.4 and 12.5 years, respectively. First, we fit Cox proportional hazards models and used the change in likelihood ratio (Δ LR) to determine the additional prognostic information provided by signatures beyond that of (i) Ki67 and (ii) IHC subtypes. Second and uniquely, we then assessed whether signatures could compete well with pathology-based IHC classifiers by calculating the additional prognostic information of Ki67/IHC subtypes beyond signatures.
In cohort 1, only RS and PAM50 provided additional prognostic information beyond Ki67 and IHC subtypes (Δ LR-χ
Ki67: RS = 12.8, PAM50 = 20.7, IHC subtypes: RS = 12.9, PAM50 = 11.7). Conversely, IHC subtypes added prognostic information beyond all signatures except PAM50. Similar results were observed in cohort 2.
RS and PAM50 provided more prognostic information than the IHC subtypes in all breast cancer patients; however, the IHC subtypes did not add any prognostic information to PAM50.
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Continuous growth models show great potential for analysing cancer screening data. We recently described such a model for studying breast cancer tumour growth based on modelling tumour size at ...diagnosis, as a function of screening history, detection mode, and relevant patient characteristics. In this article, we describe how the approach can be extended to jointly model tumour size and number of lymph node metastases at diagnosis. We propose a new class of lymph node spread models which are biologically motivated and describe how they can be extended to incorporate random effects to allow for heterogeneity in underlying rates of spread. Our final model provides a dramatically better fit to empirical data on 1860 incident breast cancer cases than models in current use. We validate our lymph node spread model on an independent data set consisting of 3961 women diagnosed with invasive breast cancer.
Mammographic density is a strong risk factor for breast cancer and an important determinant of screening sensitivity, but its clinical utility is hampered due to the lack of objective and automated ...measures. We evaluated the performance of a fully automated volumetric method (Volpara).
A prospective cohort study included 41,102 women attending mammography screening, of whom 206 were diagnosed with breast cancer after a median follow-up of 15.2 months. Percent and absolute dense volumes were estimated from raw digital mammograms. Genotyping was performed in a subset of the cohort (N = 2,122). We examined the agreement by side and view and compared density distributions across different mammography systems. We also studied associations with established density determinants and breast cancer risk.
The method showed good agreement by side and view, and distributions of percent and absolute dense volume were similar across mammography systems. Volumetric density was positively associated with nulliparity, age at first birth, hormone use, benign breast disease, and family history of breast cancer, and negatively with age and postmenopausal status. Associations were also observed with rs10995190 in the ZNF365 gene (P < 1.0 × 10(-6)) and breast cancer risk HR for the highest vs. lowest quartile, 2.93; 95% confidence interval, 1.73-4.96 and 1.63 (1.10-2.42) for percent and absolute dense volume, respectively.
In a high-throughput setting, Volpara performs well and in accordance with the behavior of established density measures.
Automated measurement of volumetric mammographic density is a promising tool for widespread breast cancer risk assessment.
Because the incidence of breast cancer is increasing and prognosis is improving, a growing number of women are at risk of developing bilateral disease. Little is known, however, about incidence ...trends and prognostic features of bilateral breast cancer.
Among 123,757 women with a primary breast cancer diagnosed in Sweden from 1970 to 2000, a total of 6,550 developed bilateral breast cancer. We separated synchronous (diagnosed within 3 months after a first breast cancer) and metachronous bilateral cancer, and analyzed incidence and mortality rates of breast cancer using Poisson regression models.
The incidence of synchronous breast cancer increased by age and by 40% during the 1970s, whereas the incidence of metachronous cancer decreased by age and by approximately 30% since the early 1980s, most likely due to increasing use of adjuvant therapy. Women who developed bilateral cancer within 5 years and at age younger than 50 years were 3.9 times (95% CI, 3.5 to 4.5) more likely to die as a result of breast cancer than women with unilateral cancer. Women with a bilateral cancer diagnosed more than 10 years after the first cancer had a prognosis similar to that of a unilateral breast cancer. Adjuvant chemotherapy of primary cancer is a predictor of poor survival after diagnosis of early metachronous cancers.
We found profound differences in the incidence trends and prognostic outlook between synchronous and metachronous bilateral breast cancer diagnosed at different ages. Adjuvant chemotherapy therapy has a dual effect on metachronous cancer: it reduces the risk, while at the same time it seems to worsen the prognosis.
Breast cancer patients who have not previously attended mammography screening may be more likely to discontinue adjuvant hormone therapy and therefore have a worse disease prognosis.
We conducted a ...population-based cohort study using data from Stockholm Mammography Screening Program, Stockholm-Gotland Breast Cancer Register, Swedish Prescribed Drug Register, and Swedish Cause of Death Register. Women in Stockholm who were diagnosed with breast cancer between 2001 and 2008 were followed until December 31, 2015. Non-participants of mammography screening were defined as women who, prior to their breast cancer diagnosis, were invited for mammography screening but did not attend.
Of the 5098 eligible breast cancer patients, 4156 were defined as screening participants and 942 as non-participants. Compared with mammography screening participants, non-participants were more likely to discontinue adjuvant hormone therapy, with an adjusted hazard ratio (HR) of 1.30 (95% CIs, 1.11 to 1.53). Breast cancer patients not participating in mammography screening were also more likely to have worse disease-free survival, even after adjusting for tumor characteristics and other covariates (adjusted HR 1.22 (95% CIs, 1.05 to 1.42 for a breast cancer event).
Targeted interventions to prevent discontinuation of adjuvant hormone therapy are needed to improve breast cancer outcomes among women not attending mammography screening.
Mammographic density (MD) is a strong and heritable intermediate phenotype of breast cancer, but much of its genetic variation remains unexplained.
We conducted a genetic association study of ...volumetric MD in a Swedish mammography screening cohort (n = 9498) to identify novel MD loci. Associations with volumetric MD phenotypes (percent dense volume, absolute dense volume, and absolute nondense volume) were estimated using linear regression adjusting for age, body mass index, menopausal status, and six principal components. We also estimated the proportion of MD variance explained by additive contributions from single-nucleotide polymorphisms (SNP-based heritability h
) in 4948 participants of the cohort.
In total, three novel MD loci were identified (at P < 5 × 10
): one for percent dense volume (HABP2) and two for the absolute dense volume (INHBB, LINC01483). INHBB is an established locus for ER-negative breast cancer, and HABP2 and LINC01483 represent putative new breast cancer susceptibility loci, because both loci were associated with breast cancer in available meta-analysis data including 122,977 breast cancer cases and 105,974 control subjects (P < 0.05). h
(SE) estimates for percent dense, absolute dense, and nondense volume were 0.29 (0.07), 0.31 (0.07), and 0.25 (0.07), respectively. Corresponding ratios of h
to previously observed narrow-sense h
estimates in the same cohort were 0.46, 0.72, and 0.41, respectively.
These findings provide new insights into the genetic basis of MD and biological mechanisms linking MD to breast cancer risk. Apart from identifying three novel loci, we demonstrate that at least 25% of the MD variance is explained by common genetic variation with h
/h
ratios varying between dense and nondense MD components.
Biomarkers for early detection of breast cancer may complement population screening approaches to enable earlier and more precise treatment. The blood proteome is an important source for biomarker ...discovery but so far, few proteins have been identified with breast cancer risk. Here, we measure 2929 unique proteins in plasma from 598 women selected from the Karolinska Mammography Project to explore the association between protein levels, clinical characteristics, and gene variants, and to identify proteins with a causal role in breast cancer. We present 812 cis-acting protein quantitative trait loci for 737 proteins which are used as instruments in Mendelian randomisation analyses of breast cancer risk. Of those, we present five proteins (CD160, DNPH1, LAYN, LRRC37A2 and TLR1) that show a potential causal role in breast cancer risk with confirmatory results in independent cohorts. Our study suggests that these proteins should be further explored as biomarkers and potential drug targets in breast cancer.
Background Experimental studies indicate that neuroendocrine pathways might play a role in progression of breast cancer. We aim to test the hypothesis that somatic mutations in the genes of ...neuroendocrine pathways influence breast cancer prognosis, through dysregulated gene expression in tumor tissue. Methods We conducted an extreme case-control study including 208 breast cancer patients with poor invasive disease-free survival (iDFS) and 208 patients with favorable iDFS who were individually matched on molecular subtype from the Breast Cancer Cohort at West China Hospital (WCH; N = 192) and The Cancer Genome Atlas (TCGA; N = 224). Whole exome sequencing and RNA sequencing of tumor and paired normal breast tissues were performed. Adrenergic, glucocorticoid, dopaminergic, serotonergic, and cholinergic pathways were assessed for differences in mutation burden and gene expression in relation to breast cancer iDFS using the logistic regression and global test, respectively. Results In the pooled analysis, presence of any somatic mutation (odds ratio = 1.66, 95% CI: 1.07-2.58) of the glucocorticoid pathway was associated with poor iDFS and a two-fold increase of tumor mutation burden was associated with 17% elevated odds (95% CI: 2-35%), after adjustment for cohort membership, age, menopausal status, molecular subtype, and tumor stage. Differential expression of genes in the glucocorticoid pathway in tumor tissue (P = 0.028), but not normal tissue (P = 0.701), was associated with poor iDFS. Somatic mutation of the adrenergic and cholinergic pathways was significantly associated with iDFS in WCH, but not in TCGA. Conclusion Glucocorticoid pathway may play a role in breast cancer prognosis through differential mutations and expression. Further characterization of its functional role may open new avenues for the development of novel therapeutic targets for breast cancer. Keywords: Breast cancer, Somatic mutation, Differential expression, Pathway
High mammographic density is associated with breast cancer and with delayed detection. We have examined whether localized density, at the site of the subsequent cancer, is independently associated ...with being diagnosed with a large-sized or interval breast cancer.
Within a prospective cohort of 63,130 women, we examined 891 women who were diagnosed with incident breast cancer. For 386 women, retrospective localized density assessment was possible. The main outcomes were interval cancer vs. screen-detected cancer and large (> 2 cm) vs. small cancer. In negative screening mammograms, overall and localized density were classified reflecting the BI-RADS standard. Density concordance probabilities were estimated through multinomial regression. The associations between localized density and the two outcomes were modeled through logistic regression, adjusted for overall density, age, body mass index, and other characteristics.
The probabilities of concordant localized density were 0.35, 0.60, 0.38, and 0.32 for overall categories "A," "B," "C," and "D." Overall density was associated with large cancer, comparing density category D to A with OR 4.6 (95%CI 1.8-11.6) and with interval cancer OR 31.5 (95%CI 10.9-92) among all women. Localized density was associated with large cancer at diagnosis with OR 11.8 (95%CI 2.7-51.8) among all women and associated with first-year interval cancer with OR 6.4 (0.7 to 58.7) with a significant linear trend p = 0.027.
Overall density often misrepresents localized density at the site where cancer subsequently arises. High localized density is associated with interval cancer and with large cancer. Our findings support the continued effort to develop and examine computer-based measures of localized density for use in personalized breast cancer screening.
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