Outcome of breast cancer patients with low hormone receptor positivity: analysis of a 15-year population-based cohort.

BACKGROUND: Guideline recommendations for the treatment of breast cancer with low hormone receptor (HR) expression (1%-9%) are ambiguous and several studies showed more similarities with HR-negative tumors than with HR strongly positive tumors (≥10%). We used a population-based 15-year cohort to compare patient characteristics and outcome of HR low positive tumors with HR-negative and HR strongly positive tumors, respectively. PATIENTS AND METHODS: A total of 38  560 women diagnosed with early invasive breast cancer between 2004 and 2018 within the scope of the Munich Cancer Registry with 4.9 million inhabitants were included. Descriptive analyses of prognostic factors, treatment, and outcome analyses using the Kaplan-Meier method; cumulative incidence in consideration of competing risks; and multivariate analyses (Cox regression and Fine-Gray model) were conducted. Endpoints were time to local recurrence (TTLR), time to lymph node recurrence (TTLNR), time to metastasis (TTM), overall survival (OS), and relative survival (RS). RESULTS: A total of 861 patients (2%) had HR low positive, 4862 (13%) HR-negative, and 32  837 (85%) HR strongly positive tumors. Within the HER2-negative cohort (n = 33  366), survival of HR low positive tumors was significantly worse than that of HR strongly positive tumors [OS hazard ratio 0.66 (95% confidence interval 0.55-0.78)], whereas between HR low positive and HR-negative tumors no significant survival difference could be detected [OS hazard ratio 0.93 (95% confidence interval 0.78-1.11)]. TTLR, TTLNR, and TTM showed similar results. By contrast, within the HER2-positive cohort (n = 5194), no statistically significant differences between the three HR groups could be detected in multivariate analyses. CONCLUSION: Current definitions for HR positivity and its clinical relevance should be reconsidered. Patients with HR low positive/HER2-negative tumors could be regarded and treated similar to patients with triple-negative tumors.

Endocrine sensitivity is decisive for patient outcome in small node-negative breast cancers (BC) (pT1a,b) - results from the Munich Cancer Registry.

PURPOSE: In clinical routine, adjuvant systemic therapy in small node-negative (N0) BC is controversial, in particular in HER2-positive disease. We aimed to evaluate outcome of consecutive patients with small N0 BC in a population-based cancer registry and thus consequently substantiate indications for chemotherapy in those patient subgroups at increased relapse risk or poor survival. METHODS: From 2002 to 2009 (median follow-up 6 years), 9707 primary breast cancer patients with N0 tumors <2 cm (pTis, pT1N0M0) were reported to the Munich Cancer Registry. Patients with pTis tumors (n = 1870) served as internal comparator. Time to progression, observed (OS) and relative survival rates (Kaplan-Meier estimates) are presented. Cox regression analysis was used to assess the influence of tumor size, age, HR-, and HER2-status. RESULTS: 10-year-OS for pTis was 94.0%. In HR-positive tumors it was 91.9% in pT1a, 90.6% in pT1b, and 86.8% in pT1c. In HR-negative tumors, rates were 91.7%, 86.8%, and 86.8%, respectively. In HER2-positive tumors it was 81.2%, 88.1%, and 86.7%, in HER2-negative 93.1%, 90.6%, and 86.0%, respectively. In the multivariate model, age, tumor size, and HR-status showed a significant impact on OS (HRneg. vs. HRpos.: hazard ratio 1.50 (95% CI; 1.12-1.99), while HER2-status was not an independent prognostic factor. CONCLUSION: Prognosis of N0 tumors <1 cm is excellent, especially if they are HR-positive, even in HER2-positive cases. Weighing potential benefits vs. side-effects, there seems to be no need for chemotherapy in tumors <0.5 cm. In pT1b chemotherapy may be considered, if tumors are triple negative or HER2-positive and HR-negative. In pT1c guideline-based adjuvant therapy using all therapeutic options seems to be warranted.

Is primary surgery of breast cancer patients consistent with German guidelines? Twelve-year trend of population-based clinical cancer registry data.

This population-based analysis aimed to describe the 12-year trend of primary surgery following the introduction of national guidelines for the management of breast cancer in Germany, thus the implementation of breast-conserving surgery (BCS) for pT1/2-tumours and the implementation of sentinel lymph node biopsy (SLNB). Cancer registry data from 72 742 breast cancer patients diagnosed between 1999 and 2010 in four different regions in Germany were used. Descriptive statistics and multivariate logistic regression analysis were conducted. Between 1999 and 2010, rates of BCS for pT1/2-tumours rose from 60.5% to 79.9%, rates of SLNB increased rapidly from 0.4% to 79.0%. Both surgical therapies were already adherent to the respective guidelines, although some regional differences could be observed: in 1999-2003, the chance of BCS was 2.6-fold higher [odds ratio (OR) 2.6] in the western regions than in the eastern regions, but this difference decreased over time (2004-2007 OR 1.6; 2008-2010 OR 1.2). A similar pattern was observable for SLNB: in 1999-2003, the chance of receiving SLNB was 4.4-fold higher in the western regions, but these rates converged (2004-2007 OR 3.7; 2008-2010 OR 1.5). The further increase of BCS- and SLNB rates after publication of guidelines and the reduction of regional differences may also be attributable to guideline implementation.

[Changes in therapy for breast cancer patients as a result of mammography screening. An analysis of Bavarian cancer registry data from 2000 to 2008]. / Veränderungen der Therapie des Mammakarzinoms in Bayern seit Einführung des Mammografie-Screenings. Eine Analyse bayerischer Krebsregisterdaten der Jahre 2000 bis 2008.

PURPOSE: A quality controlled mammography screening programme was initiated at the end of 2003 in Bavaria, a region with 12.5 million inhabitants, and transferred over to the national screening programme at the end of 2006. The purpose of this study was to evaluate immediate population-based consequences of mammography screening on breast cancer therapy. METHODS: Data from 75 475 breast cancer cases, diagnosed between 2000 and 2008 and registered in one of the 6 Bavarian clinical cancer registries were analysed. 51.4% of these patients were between 50 and 69 years of age and therefore the target population for screening. Trends of prognostic factors and standard therapies were calculated for 3 age groups (≤49 years, 50-69 years, ≥70 years) by means of annual percentages as well as 95%-confidence intervals for the percent difference between 2000 and 2008 (year of diagnosis). For interpretation of therapy trends, logistic regression models were calculated. RESULTS: Therapy trends showed that the increasingly favourable stage distribution may have resulted in the reduction of more radical surgical methods such as mastectomy (2000: 32.6%; 2008: 19.6%) or axillary dissection (89.0% vs. 37.0%), especially for women aged 50-69. An increase of radiation therapies (59.7% vs. 66.6%) can be explained to some extent by the increase in breast conserving surgeries. The shift to more favourable prognostic factors led, in accordance with the guidelines, to an increase of the proportion of singular endocrine therapies (28.5% vs. 40.7%), a decrease of chemotherapies (20.4% vs. 13.1%) and therefore to more gentle systemic therapies overall. These trends strengthened in the years following the introduction of screening, with a simultaneous rise of screening participants in the target population. CONCLUSION: The introduction of mammography screening in Bavaria has already shown the expected trend towards more favourable prognostic factors. Among other things, this could be a reason for the increasing use of more gentle therapies. Whether the screening in Bavaria leads to a mortality reduction, has to be analysed on the basis of an initial comparison of participation status followed by the trends in mortality thereafter.

A PheWAS approach in studying HLA-DRB1*1501.

HLA-DRB1 codes for a major histocompatibility complex class II cell surface receptor. Genetic variants in and around this gene have been linked to numerous autoimmune diseases. Most notably, an association between HLA-DRB1*1501 haplotype and multiple sclerosis (MS) has been defined. Utilizing electronic health records and 4235 individuals within Marshfield Clinic's Personalized Medicine Research Project, a reverse genetic screen coined phenome-wide association study (PheWAS) tested association of rs3135388 genotype (tagging HLA-DRB1*1501) with 4841 phenotypes. As expected, HLA-DRB1*1501 was associated with MS (International Classification of Disease version 9-CM (ICD9) 340, P=0.023), whereas the strongest association was with alcohol-induced cirrhosis of the liver (ICD9 571.2, P=0.00011). HLA-DRB1*1501 also demonstrated association with erythematous conditions (ICD9 695, P=0.0054) and benign neoplasms of the respiratory and intrathoracic organs (ICD9 212, P=0.042), replicating previous findings. This study not only builds on the feasibility/utility of the PheWAS approach, represents the first external validation of a PheWAS, but may also demonstrate the complex etiologies associated with the HLA-DRB1*1501 loci.

Surgical treatment of early stage breast cancer in elderly: an international comparison.

Over 40% of breast cancer patients are diagnosed above the age of 65. Treatment of these elderly patients will probably vary over countries. The aim of this study was to make an international comparison (several European countries and the US) of surgical and radiation treatment for elderly women with early stage breast cancer. Survival comparisons were also made. Data were obtained from national or regional population-based registries in the Netherlands, Switzerland, Ireland, Belgium, Germany, and Portugal. For the US patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Early stage breast cancer patients aged ≥ 65 diagnosed between 1995 and 2005 were included. An international comparison was made for breast and axillary surgery, radiotherapy after breast conserving surgery (BCS), and relative or cause-specific survival. Overall, 204.885 patients were included. The proportion of patients not receiving any surgery increased with age in many countries; however, differences between countries were large. In most countries more than half of all elderly patients received breast conserving surgery (BCS), with the highest percentage in Switzerland. The proportion of elderly patients that received radiotherapy after BCS decreased with age in all countries. Moreover, in all countries the proportion of patients who do not receive axillary surgery increased with age. No large differences in survival between countries were recorded. International comparisons of surgical treatment for elderly women with early stage breast cancer are scarce. This study showed large international differences in treatment of elderly early stage breast cancer patients, with the most striking result the large proportion of elderly who did not undergo surgery at all. Despite large treatment differences, survival does not seem to be affected in a major way.

Detailed genetic characterization of the interleukin-23 receptor in psoriasis.

Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (>2800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR(common)=0.67; P(comb)=4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P(Het)=0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.

Variants in the 5q31 cytokine gene cluster are associated with psoriasis.

A multitiered genetic association study of 25 215 single-nucleotide polymorphisms (SNPs) in three case-control sample sets (1446 patients and 1432 controls) identified three IL13-linked SNPs (rs1800925, rs20541 and rs848) associated with psoriasis. Although the susceptibility effects at these SNPs were modest (joint allelic odds ratios (ORs): 0.76 to 0.78; P(comb): 1.3E-03 to 2.50E-04), the association patterns were consistent across the sample sets, with the minor alleles being protective. Haplotype analyses identified one common, susceptible haplotype CCG (joint allelic OR=1.27; P(comb)=1.88E-04) and a less common, protective haplotype TTT (joint allelic OR=0.74; P(comb)=7.05E-04). In combination with the other known genetic risk factors, HLA-C, IL12B and IL23R, the variants reported here generate an 11-fold psoriasis-risk differential. Residing in the 5q31 cytokine gene cluster, IL13 encodes an important T-cell-derived cytokine that regulates cell-mediated immunity. These results provide the foundation for additional studies required to fully dissect the associations within this cytokine-rich genomic region, as polymorphisms in closely linked candidate genes, such as IRF1, IL5 or IL4, may be driving these results through linkage disequilibrium.