Interval breast cancer is associated with interferon immune response.

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.

Association between breast cancer risk and disease aggressiveness: Characterizing underlying gene expression patterns.

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.

Differential Burden of Rare and Common Variants on Tumor Characteristics, Survival, and Mode of Detection in Breast Cancer.

Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes-or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer-specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16-2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21-2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (<25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12-3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64-0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection.Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329-38. ©2018 AACR.

Risk and predictors of psoriasis in patients with breast cancer: a Swedish population-based cohort study.

BACKGROUND: The risk of psoriasis in patients with breast cancer is largely unknown, as available evidence is limited to case findings. We systematically examined the incidence and risk factors of psoriasis in patients with breast cancer. METHODS: A Swedish nationwide cohort of 56,235 breast cancer patients (2001-2012) was compared to 280,854 matched reference individuals from the general population to estimate the incidence and hazard ratio (HR) of new-onset psoriasis. We also calculated HRs for psoriasis according to treatment, genetic, and lifestyle factors in a regional cohort of 8987 patients. RESULTS: In the nationwide cohort, 599 patients with breast cancer were diagnosed with psoriasis during a median follow-up of 5.1 years compared to 2795 cases in the matched reference individuals. This corresponded to an incidence rate of 1.9/1000 person-years in breast cancer patients vs. 1.7/1000 person-years in matched reference individuals. Breast cancer patients were at an increased risk of psoriasis (HR = 1.17; 95% confidence interval (CI) = 1.07-1.28), especially its most common subtype (psoriasis vulgaris; HR = 1.33; 95% CI = 1.17-1.52). The risk of psoriasis vulgaris was highest shortly after diagnosis but remained increased up to 12 years. Treatment-specific analyses indicated a higher risk of psoriasis in patients treated with radiotherapy (HR = 2.44; 95% CI = 1.44-4.12) and mastectomy (HR = 1.54, 95% CI = 1.03-2.31). Apart from treatment-specific effects, we identified genetic predisposition, obesity, and smoking as independent risk factors for psoriasis in breast cancer patients. CONCLUSIONS: The incidence of psoriasis is slightly elevated among patients with breast cancer, with treatment, lifestyle, and genetic factors defining the individual risk profile.

Common shared genetic variation behind decreased risk of breast cancer in celiac disease.

There is epidemiologic evidence showing that women with celiac disease have reduced risk of later developing breast cancer, however, the etiology of this association is unclear. Here, we assess the extent of genetic overlap between the two diseases. Through analyses of summary statistics on densely genotyped immunogenic regions, we show a significant genetic correlation (r = -0.17, s.e. 0.05, P < 0.001) and overlap (P permuted < 0.001) between celiac disease and breast cancer. Using individual-level genotype data from a Swedish cohort, we find higher genetic susceptibility to celiac disease summarized by polygenic risk scores to be associated with lower breast cancer risk (ORper-SD, 0.94, 95% CI 0.91 to 0.98). Common single nucleotide polymorphisms between the two diseases, with low P-values (P CD < 1.00E-05, P BC ≤ 0.05), mapped onto genes enriched for immunoregulatory and apoptotic processes. Our results suggest that the link between breast cancer and celiac disease is due to a shared polygenic variation of immune related regions, uncovering pathways which might be important for their development.

Gastrointestinal symptoms and weight loss in cancer patients receiving chemotherapy.

Cancer patients receiving chemotherapy have a high risk of malnutrition secondary to the disease and treatment, and 40-80 % of cancer patients suffer from different degrees of malnutrition, depending on tumour subtype, location, staging and treatment strategy. Malnutrition in cancer patients affects the patient's overall condition, and it increases the number of complications, the adverse effects of chemotherapy and reduces the quality of life. The aim of the present study was to evaluate weight-loss prevalence depending on the tumour site and the gastrointestinal (GI) symptoms of oncology patients receiving chemotherapy. We included 191 cancer patients receiving chemotherapy. Files of all patients were reviewed to identify symptoms that might potentially influence weight loss. The nutritional status of all patients was also determined. The cancer sites in the patients were as follows: breast (31·9 %); non-colorectal GI (18·3 %); colorectal (10·4 %); lung (5·8 %); haematological (13·1 %); others (20·5 %). Of these patients, 58 % experienced some degree of weight loss, and its prevalence was higher among the non-colorectal GI and lung cancer patients. Common symptoms included nausea (59·6 %), anorexia (46 %) and constipation (31·9 %). A higher proportion of patients with ≥ 5 % weight loss experienced anorexia, nausea and vomiting (OR 9·5, 2·15 and 6·1, respectively). In conclusion, these results indicate that GI symptoms can influence weight loss in cancer patients, and they should be included in early nutritional evaluations.