Rassegna della letteratura – marzo 2019

Biologia – Genetica – Laboratorio – Anatomia patologica

Li M, Guo Y, Feng YM, Zhang N – Identification of Triple-Negative Breast Cancer Genes and a Novel High-Risk Breast Cancer Prediction Model Development Based on PPI Data and Support Vector Machines. – Front Genet. 2019 Mar 15;10:180. doi: 10.3389/fgene.2019.00180

Triple-negative breast cancer (TNBC) is a special subtype of breast cancer that is difficult to treat. It is crucial to identify breast cancer-related genes that could provide new biomarkers for breast cancer diagnosis and potential treatment goals. In the development of our new high-risk breast cancer prediction model, seven raw gene expression datasets from the NCBI gene expression omnibus (GEO) database (GSE31519, GSE9574, GSE20194, GSE20271, GSE32646, GSE45255, and GSE15852) were used. Using the maximum relevance minimum redundancy (mRMR) method, we selected significant genes. Then, we mapped transcripts of the genes on the protein-protein interaction (PPI) network from the Search Tool for the Retrieval of Interacting Genes (STRING) database, as well as traced the shortest path between each pair of proteins. Genes with higher betweenness values were selected from the shortest path proteins. In order to ensure validity and precision, a permutation test was performed. We randomly selected 248 proteins from the PPI network for shortest path tracing and repeated the procedure 100 times. We also removed genes that appeared more frequently in randomized results. As a result, 54 genes were selected as potential TNBC-related genes. Using 14 out the 54 genes, which are potential TNBC associated genes, as input features into a support vector machine (SVM), a novel model was trained to predict high-risk breast cancer. The prediction accuracy of normal tissues and TNBC tissues reached 95.394%, and the predictions of Stage II and Stage III TNBC reached 86.598%, indicating that such genes play important roles in distinguishing breast cancers, and that the method could be promising in practical use. According to reports, some of the 54 genes we identified from the PPI network are associated with breast cancer in the literature. Several other genes have not yet been reported but have functional resemblance with known cancer genes. These may be novel breast cancer-related genes and need further experimental validation. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to appraise the 54 genes. It was indicated that cellular response to organic cyclic compounds has an influence in breast cancer, and most genes may be related with viral carcinogenesis

s of recommended treatment in breast cancer care in Norway and to improve the quality of epidemiological data, the Cancer Registry of Norway (CRN) in cooperation with the Norwegian Breast Cancer Group (NBCG) developed the Norwegian Breast Cancer Registry (NBCR). The objective of this study is to assess the feasibility of using the NBCR for estimating the EUSOMA QI individually for all hospitals diagnosing and treating breast cancer in Norway.ù

Methods: To provide researchers with high quality cancer data as well as for the purpose of national cancer statistics, the CRN employs a cancer registry system to 1) longitudinal capture data from all patients from all medical entities that diagnose and/or treat cancer patients (e.g., pathology, radiology and clinical departments) in Norway; 2) curate data, i.e. validate the correctness of collected data, and assemble the validated cancer data as cancer cases; 3) provide data for analytics and presentation. Estimates for 10 EUSOMA QI were calculated at national and hospital level. To compare hospitals, a summary score of QIs was defined for each hospital.

Results: All hospitals currently treating breast cancer patients have the technical ability to submit data to the NBCR for estimation of QIs defined by EUSOMA. Data from pathology and surgery are of high quality. However, data from oncological and radiological departments are incomplete, but improving. This currently hinders three QIs from being calculated. QI on benign to malign diagnosis needs to be calculated at the individual Breast Centre. Over time the adherence to guidelines have improved and the hospital variation for the respective QI have decreased. Two hospitals met all minimum standard on ten QIs in year 2016 and one hospital did not meet one minimum standard, but met all other targets.

Conclusion: The NBCR has since 2012 published annual reports on breast cancer care and for the year 2016 measured 10 of 14 QI defined by EUSOMA. Increased compliance of recommended treatment in Norway has been observed during the years the registry has been active.

Lee A, Jo S, Lee C, et Al. – Diabetes as a prognostic factor in HER-2 positive breast cancer patients treated with targeted therapy. – Breast Cancer. 2019 Mar 29. doi: 10.1007/s12282

Background: Recent studies revealed that metabolic stress influences the outcomes of breast cancer treatment. We sought to evaluate the prognostic effect of type 2 diabetes and find the molecular mechanism of relapses in postoperative HER-2+ breast cancer patients treated with HER-2 targeted therapy.

Methods: We evaluated 190 HER-2+ breast cancer patients (pT1-4N0-2M0) who were treated with surgical resection and trastuzumab (HER-2 targeted therapy) between 2006 and 2015. Survival outcomes and failure patterns were compared between such patients with (n = 12) and without (n = 178) type 2 diabetes.

Results: The median follow-up period was 42.4 months (range 12.0-124.7 months). Twenty-one patients (11.1%) showed relapse (including nine patients with locoregional failure), and three patients (1.6%) died as a result of cancer relapse. One-third of the patients with diabetes experienced relapse (4/12, 33.3%). The 3-year disease-free survival (DFS) and overall survival (OS) rates were 90.7% and 98.6%, respectively. Diabetic patients showed shorter DFS compared with non-diabetic patients (p = 0.006, 74.1% vs. 91.9%). OS was also shorter in diabetic patients compared with non-diabetic patients (p = 0.017, 91.7% vs. 99.1%). Of our interest, the levels of HER-3 and its ligand neuregulin-1 were significantly increased in the tumor specimen in HER-2+ breast cancer patients suffering with type 2 diabetes than that in the euglycemic control group.

Conclusion: Type 2 diabetes was associated with detrimental effects on survival in postoperative HER-2+ breast cancer patients who were treated with trastuzumab. The poor prognostic effect of diabetes in HER-2+ breast cancer patients could be associated with the high levels of HER-3 and neuregulin 1, thus it should be considered and evaluated more.

Takala S, Nevanlinna H et Al. – Metaplastic carcinoma of the breast: Prognosis and response to systemic treatment in metastatic disease. Breast J. 2019 Mar 29. doi: 10.1111/tbj.13234.

Background: Metaplastic breast carcinomas (MpBCs) are rare, aggressive breast cancers. Due to the scant literature of this disease most guidelines do not give recommendation for this entity. The aim of the study was to review the clinicopathologic features, treatment, and outcomes of the patients with MpBC treated at our institution.

Methods: We searched databases for patients with histologically confirmed MpBC from 2002 to 2016.

Results: A total of 78 patients with MpBC were included in the study. All histological material was reviewed by an experienced breast pathologist. Most tumors were grade 3 (83%) and triple negative (85%). Eighty-two percent were node negative. Sixty-four percent received adjuvant chemotherapy. The 5-year disease free survival was 63% and 5-year breast cancer specific overall survival was 61%. Tumor size and mixed metaplastic histology were associated with worse outcome in this patient group. One third of the patients (n = 28) had metastatic disease at initial presentation or developed metastases at follow-up. The lungs were the most common site of first distant recurrence. Half (n = 14) of these patients received palliative chemotherapy. Of those only 6% (n = 2) had partial response and 18% had stable disease as best response to treatment. The median overall survival time with metastatic disease was only 3.4 months.

Conclusion: MpBC is an aggressive type of breast cancer with poor outcome despite low nodal involvement and aggressive local and systemic therapy. Tumor response to palliative systemic chemotherapy remains poor for MpBC patients

Thomsen C, Nielsen S, Nielsen BS et Al. – Estrogen Receptor-α Quantification in Breast Cancer: Concordance Between Immunohistochemical Assays and mRNA-In Situ Hybridization for ESR1 Gene.   Appl Immunohistochem Mol Morphol. 2019 Mar 27. doi: 10.1097/PAI.0000000000000760

Immunohistochemical (IHC) quantification of estrogen receptor-α (ER) is used for assessment of treatment regimen in breast cancer. Different ER IHC assays may produce diverging results, because of different antibody clones, protocols, and stainer platforms. Objective tissue-based techniques to assess sensitivity and specificity of IHC assays are therefore needed. We tested the usability of ER mRNA-in situ hybridization (mRNA-ISH) in comparison with assays based on clones SP1 and 6F11. We selected 56 archival specimens according to their reported ER IHC positivity, representing a wide spectrum from negative to strongly positive cases. The specimens were used to prepare 4 TMAs with 112 cores. Serial sections of each TMA were stained for ER and pan-cytokeratin (PCK) by IHC and ESR1 (ER gene) by mRNA-ISH. Digital image analysis (DIA) was used to determine ER IHC H-score. ESR1 mRNA-ISH was scored both manually and by DIA. DIA showed a nonlinear correlation between IHC and ESR1 mRNA-ISH with R-values of 0.80 and 0.78 for the ER antibody clones SP1 and 6F11, respectively. Comparison of manual mRNA-ISH scoring categories and SP1 and 6F11 IHC H-scores showed a highly significant relationship (P<0.001). In conclusion, the study showed good correlation between mRNA-ISH and IHC, suggesting that mRNA-ISH can be a valuable tool in the assessment of the sensitivity and specificity of ER IHC assays.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited.

Wang B, Yang Y, Jiang Z – Clinicopathological characteristics, diagnosis, and prognosis of pregnancy-associated breast cancer. – Thorac Cancer. 2019 Mar 28. doi: 10.1111/1759-7714.13045

Background: The aim of this study was to evaluate the characteristics, diagnosis, prognosis, and effective treatment modalities of pregnancy-associated breast cancer (PABC).

Methods: From 1 January 2005 to 31 December 2015, 142 patients with PABC were identified in the Cancer Institute and Hospital of Tianjin Medical University database. The clinicopathological features, treatment methods, and outcomes were retrospectively evaluated

Results: The median age at diagnosis was 30 years. All patients presented with a palpable mass in the breast. The sensitivity of ultrasound and mammography in PABC diagnosis was 86% and 83.3%, respectively, which increased to 91.3% when a combination of mammography and ultrasound was used. The median tumor size was 5.5 cm, and 63.1% of patients had associated axillary lymph node metastases. The proportions of ER negative, PR negative and HER2 positive were 45.7%, 45.7% and 30%, respectively. The five-year overall survival (OS) and disease-free survival (DFS) rates were 76.8% and 63.5%, respectively. According to univariate analysis, T stage, N stage, and HER2 status were significant prognostic factors for OS and DFS. The time interval between the onset of the first symptom and the first meeting with a health professional was also significant for OS. Multivariate analysis showed that T stage and HER2 status were independent prognostic risk factors for OS and DFS.

Conclusion: PABC is an aggressive form of breast cancer associated with advanced stage at diagnosis. Despite the existing difficulties in diagnosis, imaging examinations are indispensable. Early diagnosis and multidisciplinary therapy, including anti-HER2 targeted therapy, may be important to improve prognosis.

Soltani M, Rahpeima R, Kashkooli FM. – Breast cancer diagnosis with a microwave thermoacoustic imaging technique-a numerical approach. – Med Biol Eng Comput. 2019 Mar 27. doi: 10.1007/s11517

Microwave-induced thermoacoustic imaging (MITAI) is an imaging technique with great potential for detecting breast cancer at early stages. Thermoacoustic imaging (TAI) combines the advantages of both microwave and ultrasound imaging techniques. In the current study, a three-dimensional novel numerical simulation of TAI phenomenon as a multi-physics problem is investigated. In the computational domain, a biological breast tissue including three different tissue types along with a tumor is placed in a tank containing castor oil and is irradiated by a 2.45-GHz pulsed microwave source from a rectangular waveguide. The generated heat in the biological tissue due to the electromagnetic wave irradiation and its corresponding pressure gradient in the tissue because of the temperature variations are evaluated. Also, capability of the MITAI process with respect to the tumor location and size is investigated. To identify the required power level needed for producing thermoacoustic signals, different power levels of microwave sources are investigated. The study’s results demonstrate a minuscule increase in temperature as a result of the absorption of pulsed microwave energy (for example, a maximum of 0.002472 °C temperature increase in tumor with 1 cm diameter which is located in fatty tissue of breast are obtained due to an excitation pulse of 1000 W, 1 ms). This small temperature variation in the tumor produces several kilopascals of pressure variations with maximum of 0.584016 kPa in tumor. This pressure variation will produce acoustic signals, which can be detected with an array of transducers and be used for image construction. Results demonstrate that the location of tumor in breast plays a vital role on the detecting performance of MITAI. Also, it is shown that very small tumors (with the diameter of 0.5 cm) can also be detected using MITAI technique. These simulations and procedures can be used for determining the amount of produced pressure variation, the acoustic pressure magnitude, and other complicated geometries. Graphical abstract A schematic of the thermoacoustic phenomenon.

Lee K. Kruper L, Dieli-Conwright CM et Al. – The Impact of Obesity on Breast Cancer Diagnosis and Treatment. – Curr Oncol Rep. 2019 Mar 27;21(5):41. doi: 10.1007/s11912-

Obesity is a recognized risk factor for the development of breast cancer and recurrence even when patients are treated appropriately. We reviewed the literature that addresses the impact of obesity on diagnosis and the individual therapeutic interventions, and present a summary of the findings.

Compared to non-obese women with breast cancer, obese women with breast cancer have a worse disease-free and overall survival despite appropriate local and systemic therapies. In brief, obese breast cancer patients experience more complications related to surgery, radiation, and chemotherapy. Further, obese patients are at increased risk for local recurrence compared to normal-weight women. Similarly, systemic chemotherapy is less effective, even when dosed appropriately on the basis of actual weight. Overall, endocrine therapy is less effective in obese women, and there is a suggestion that aromatase inhibitors may be selectively less effective than tamoxifen. Obese women are less likely to undergo breast reconstruction than normal-weight women, and those who do have surgery experience more surgical complications. The efficacy of cancer treatments is significantly lower in obese breast cancer survivors, posing greater challenges in patient care and disease management in this patient population. Further investigations are warranted to assess the effects on treatment outcomes and optimize therapeutic mechanisms in order to successfully target breast cancer associated with obesity.

Arena V, Pennacchia I, Vecchio FM – ER-/PR+/HER2- breast cancer type shows the highest proliferative activity among all other combined phenotypes and is more common in young patients: Experience with 6643 breast cancer cases. – Breast J. 2019 Mar 27. doi: 10.1111/tbj.13236.

The characterization of breast cancer according to its proliferative activity and the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2 is a laboratory routine that has been adopted worldwide for prognostic and therapeutic purposes. By combining data on the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2, it is possible to obtain 8 tumor patterns categorized as triple-negative, nonluminal (i.e. positive for human epidermal growth factor receptor-2 with four subtypes) and luminal (negative for human epidermal growth factor receptor-2 and positive for estrogen receptor and/or progesterone receptor with three subtypes) tumors. In general, luminal tumors are associated with a higher degree of tumor differentiation and have more favorable clinical outcomes. One of the subtypes of luminal tumors has an ER-/PR+ profile. This is a rather rare tumor subtype that behaves aggressively. The aim of this work was to analyse the proliferative activity of the eight tumor subgroups to verify if the ER-/PR+ type has a higher proliferative activity than the other subtypes, which might be correlated with its more aggressive behavior. To accomplish this, we examined estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 and Ki67 data from 6643 cases of breast cancer. We found that the tumor type that was positive for only the progesterone receptor and negative for both the estrogen receptor and human epidermal growth factor receptor-2 (1.3% of all cases) had a proliferative activity that was consistently much higher than those of the other luminal subtypes.

Hartmann-Johnsen OJ, Kåresen R et Al. – Using clinical cancer registry data for estimation of quality indicators: Results from the Norwegian breast cancer registry. – Int J Med Inform. 2019 May;125:102-109. doi: 10.1016/j.ijmedinf.2019.03.004. Epub 2019 Mar 9

Background: Increased focus on quality indicators and the use of clinical registries for breast cancer for real world studies have shown higher compliance to recommended therapy and better survival. In 2010, the European Society of Breast Cancer Specialist (EUSOMA) proposed quality indicators (QI) covering diagnosis, treatment and follow-up. To become a EUSOMA certified Breast Cancer Unit, 14 specified quality indicators, in addition to other requirements, need to be met. To evaluate the compliance and results of recommended treatment in breast cancer care in Norway and to improve the quality of epidemiological data, the Cancer Registry of Norway (CRN) in cooperation with the Norwegian Breast Cancer Group (NBCG) developed the Norwegian Breast Cancer Registry (NBCR). The objective of this study is to assess the feasibility of using the NBCR for estimating the EUSOMA QI individually for all hospitals diagnosing and treating breast cancer in Norway.ù

Methods: To provide researchers with high quality cancer data as well as for the purpose of national cancer statistics, the CRN employs a cancer registry system to 1) longitudinal capture data from all patients from all medical entities that diagnose and/or treat cancer patients (e.g., pathology, radiology and clinical departments) in Norway; 2) curate data, i.e. validate the correctness of collected data, and assemble the validated cancer data as cancer cases; 3) provide data for analytics and presentation. Estimates for 10 EUSOMA QI were calculated at national and hospital level. To compare hospitals, a summary score of QIs was defined for each hospital.

Results: All hospitals currently treating breast cancer patients have the technical ability to submit data to the NBCR for estimation of QIs defined by EUSOMA. Data from pathology and surgery are of high quality. However, data from oncological and radiological departments are incomplete, but improving. This currently hinders three QIs from being calculated. QI on benign to malign diagnosis needs to be calculated at the individual Breast Centre. Over time the adherence to guidelines have improved and the hospital variation for the respective QI have decreased. Two hospitals met all minimum standard on ten QIs in year 2016 and one hospital did not meet one minimum standard, but met all other targets.

Conclusion: The NBCR has since 2012 published annual reports on breast cancer care and for the year 2016 measured 10 of 14 QI defined by EUSOMA. Increased compliance of recommended treatment in Norway has been observed during the years the registry has been active.

Chen WR, Deng JP, Wang J et Al – Impact of 21-Gene Recurrence Score on Chemotherapy Decision in Invasive Ductal Carcinoma of Breast with Nodal Micrometastases. – Cancer Res Treat. 2019 Mar 4. doi: 10.4143/crt.2018.611.

Background: The purpose of this study was to investigate the effect of 21-gene recurrence score (RS) on predicting prognosis and chemotherapy decision in node micrometastases (N1mi) breast invasive ductal carcinoma (IDC).

Methods: Patients with stage T1-2N1mi and estrogen receptor-positive IDC diagnosed between 2004 and 2015 were included. The associations of 21-gene RS with breast cancer-specific survival (BCSS), chemotherapy decision, and benefit of chemotherapy were analyzed.

Results: We identified 4,758 patients including 1,403 patients (29.5%) treated with adjuvant chemotherapy. In the traditional RS cutoffs, 2,831 (59.5%), 1,634 (34.3%), and 293 (6.2%) patients were in the low-, intermediate-, and high-risk RS groups, respectively. In 3,853 patients with human epidermal growth factor receptor-2 (HER2) status available, most patients were HER2 negative disease (98.3%). A higher RS was independently related to chemotherapy receipt, and 14.0%, 47.7%, and 77.8% of patients in the low-, intermediate-, and high-risk RS groups received chemotherapy, respectively. The multivariate analysis indicated that a higher RS was related to worse BCSS (p < 0.001). The 5-year BCSS rates were 99.3%, 97.4%, and 91.9% in patients with low-, intermediate-, and high-risk RS groups, respectively (p < 0.001). However, chemotherapy receipt did not correlate with better BCSS in low-, intermediate-, or high-risk RS groups. There were similar trends using Trial Assigning Individualized Options for Treatment RS cutoffs.

Conclusion: The 21-gene RS does predict outcome and impact on chemotherapy decision of N1mi breast IDC. Large cohort and long-term outcomes studies are needed to identify the effects of chemotherapy in N1mi patients by different 21-gene RS groups

Saavalainen L, Lassus H, But A et Al. – A cohort study of 49933 women with surgically verified endometriosis – increased incidence of breast cancer below the age of 40. – Acta Obstet Gynecol Scand. 2019 Mar 18. doi: 10.1111/aogs.13609

Background: The association between endometriosis and breast cancer is unclear. We assessed the risk of breast cancer in women with surgically verified endometriosis, with special focus on the age at cancer diagnosis, time from endometriosis diagnosis and breast cancer histology.Methods: All women with first endometriosis associated diagnoses occurring concomitantly with relevant surgical codes during 1987-2012 were retrieved from the Finnish Hospital Discharge Register in Finland. Breast cancers diagnosed after the endometriosis diagnosis were identified from the Finnish Cancer Registry. The Finnish female population served as the reference. The endometriosis cohort consisted of 49 933 women (23 210 cases of ovarian, 20 187 peritoneal and 2372 deep infiltrating endometriosis). The outcome measure was the standardized incidence ratio (SIR) with 95% confidence interval (95%CI) of breast cancer calculated for the whole cohort and for the subtypes of endometriosis, stratified by the age at breast cancer diagnosis, histology, and time from endometriosis diagnosis.

Results: The overall risk of breast cancer (1555 cases) was similar to the reference population (SIR 0.99; 95%CI 0.94 to 1.03), did not differ in types of endometriosis, and was similar for ductal and lobular breast cancer. However, the SIR of breast cancer was increased in the age group of 20-29 years (4.44; 95%CI 2.22 to 7.94), and in the age group of 30-39 years (1.28; 1.03 to 1.57). The risk of in situ breast cancer (170 cases) was increased in the entire endometriosis cohort (1.25; 1.07-1.44).

Conclusion: The overall risk of breast cancer in women with surgically verified endometriosis was similar to that of general population. However, the risk of breast cancer at young age was increased. Young women with surgically verified endometriosis represent highly symptomatic patients with more frequent surgeries and additional therapies that might also contribute to the risk of breast cancer. This article is protected by copyright. All rights reserved.