Marjanka K. Schmidt

The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age

BACKGROUNDnThe majority of breast cancer patients are postmenopausal women who are increasingly being offered adjuvant chemotherapy. Since the beneficial effect of chemotherapy in postmenopausal patients predominantly occurs in the first 5 years after diagnosis, a prognostic marker for early events can be of use for adjuvant treatment decision making. The aim of this study was to evaluate the prognostic value of the 70-gene prognosis signature for early events in postmenopausal patients.nnnMETHODSnFrozen tumor samples from 148 patients aged 55-70 years were selected (T1-2, N0) and classified by the 70-gene prognosis signature (MammaPrint) into good or poor prognosis. Eighteen percent received hormonal therapy.nnnRESULTSnBreast cancer-specific survival (BCSS) at 5 years was 99% for the good-prognosis signature versus 80% for the poor-prognosis signature group (P = 0.036). The 70-gene prognosis signature was a significant and independent predictor of BCCS during the first 5 years of follow-up with an adjusted hazard ratio of 14.4 (95% confidence interval 1.7-122.2; P = 0.01) at 5 years.nnnCONCLUSIONnThe 70-gene prognosis signature can accurately select postmenopausal patients at low risk of breast cancer-related death within 5 years of diagnosis and can be of clinical use in selecting postmenopausal women for adjuvant chemotherapy.

European evidence-based guidelines on pancreatic cystic neoplasms

Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring <40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule >5 mm, and MPD diameter >10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Purpose:CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Methods:Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.Results:The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21–2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55–1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86–4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16–1.74), indicating a lifetime risk close to the population average.Conclusion:Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016

Etiology of hormone receptor positive breast cancer differs by levels of histologic grade and proliferation

Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p‐values for case–case and case–control comparisons for risk factors in relation to levels of grade and quartiles (Q1–Q4) of KI67 were estimated using polytomous logistic regression models. Case–case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs. Q1u2009=u20091.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs. 1u2009=u20091.68 (1.31, 2.16)] and current use of combined hormone therapy (HT) and low grade [grade 3 vs. 1u2009=u20090.27 (0.16, 0.44)] tumors. In case–control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs. 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs. 0.88 (0.66, 1.16) for grade 1] and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs. 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors.

S4-2: The Risk of Contralateral Breast Cancer in BRCA1/2 Carriers Compared to Non-BRCA1/2 Carriers in an Unselected Cohort.

Background: Women who survived their first breast cancer have a higher risk to develop a new primary tumor in the contralateral breast than the risk of women in the general population to develop a first breast cancer. Especially women who carry a germline mutation in either the BRCA1 or the BRCA2 gene face a high lifetime risk of developing a synchronous or metachronous bilateral breast cancer. It is important to provide precise risk estimates of contralateral breast cancer and identify factors which predict the risk of CBC in this group of high risk women. To answer these questions, we looked at the effect of BRCA1/2-carriership and its interaction with other factors on the risk to develop a CBC in an unselected cohort of breast cancer patients. Materials and methods: We collected clinico-pathological, treatment and follow-up data for 4856 patients with unilateral, invasive breast cancer, diagnosed under the age of 50, between 1970 and 2003, in ten different hospitals throughout The Netherlands. Germline DNA was isolated from formalin-fixed paraffin-embedded tissue and patients were tested for the most prevalent pathogenic BRCA1 and BRCA2 mutations in The Netherlands. DNA and clinical data were coded before the analyses. All second primary breast tumors in the contralateral breast diagnosed more than 3 months after the diagnosis of the first breast cancer were considered as events. Preliminary results from life-table analysis and Cox Proportional Hazard models adjusted for age at diagnosis are shown here. Further statistical analyses will include competing risk analysis. Results: In 4856 patients genotyped for BRCA1/2 mutations, 206 (4.2%) carriers were identified. During a median follow-up of 9.8 years (range 0–38), 9% of the patients developed a CBC, resulting in a cumulative 15-year risk for CBC of 10.4% (95% CI = 9.25−11.7) for non-carriers and 35.4% (95% CI = 25.9−46.9) for carriers of a BRCA1 or BRCA2 mutation (HR = 4.04 (95% CI = 2.88−5.68)). Patients carrying a BRCA1/2 mutation who were diagnosed under the age of 40 with their first breast cancer experienced a cumulative 15-year risk for CBC of 52.4% (95% CI = 36.4−70.3) versus 21.3% (95% CI = 12.0−36.0) in those over the age of 40 (HR = 0.30 (95% CI = 0.14−0.65)). Furthermore, BRCA1/2 mutation carriers with a triple negative first tumor had a cumulative risk for CBC of 43.6 (95% CI = 25.1−67.7), in contrast, BRCA1/2 mutation carriers with a non-triple negative first tumor had a cumulative risk for CBC of 13.4% (95% CI = 4.21−38.4) (HR = 0.24 (95% CI = 0.07−0.86)). Age at diagnosis and triple negative status were not found to be predictors of the risk of CBC in non-carriers (HR = 0.81 (95% CI = 0.53−1.24) and HR = 1.49 (95% CI = 0.91−2.41) respectively). Discussion: In this study we identified subgroups of patients with a high risk to develop a CBC after their first breast cancer. Guidelines about treatment decisions and screening for follow-up should take into account these high risk subgroups to provide even better information and counseling for BRCA1/2 mutation carriers. On behalf of more than 20 involved authors of the BOSOM study from 10 different hospitals and institutions throughout The Netherlands. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-2.