Comparison of Breast Parenchyma in Chest Radiotreated Survivors of Hodgkin's Lymphoma and Healthy Women with Brca Mutation Carriers: A Case Control Study

Comparison of Breast Parenchyma in Chest Radiotreated Survivors of Hodgkin's Lymphoma and Healthy Women with Brca Mutation Carriers: A Case Control Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison of Breast Parenchyma in Chest Radiotreated Survivors of Hodgkin's Lymphoma and Healthy Women with Brca Mutation Carriers: A Case Control Study Filomena Emanuela Laddaga, Michele Telegrafo, Carmela Garzillo, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4427101/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Increased background parenchymal enhancement (BPE) is an imaging biomarker of higher risk of BC. The aim of this prospective study was to evaluate the distribution of BPE patterns and the possible onset of BC in long-term HL survivors treated with chemotherapy and RT and to compare them with age-matched women with BRCA mutation carriers and without a history of cancer. 62 women, long-term survivors of HL for at least 15 years and 62 consecutive women of the same age with BRCA mutation carriers, underwent screening with dynamic contrast magnetic resonance imaging. BPE was comparable in the two groups: 31 cases (50%) of moderate and marked BPE in the long-surviving HL group and 30 (48%) in the BRCA carrier control group. In the long-surviving HL group, 3 (5%) malignant lesions were found, two of these (ductal carcinoma in situ-DCIS, n = 1; non-special type-NST, n = 1) had moderate BPE lesions in the contralateral breast and one (NST ) marked BPE. We found a BPE comparable to healthy women at high risk for BC with BRCA mutation carriers. Future research should be directed at examining the underlying cancer biology and genetic susceptibility of treatment-induced tumors. Hodgkin long term survivors late toxicity radiotherapy Breast cancer Figures Figure 1 Figure 2 Introduction Currently, Hodgkin lymphoma (HL) has an excellent clinical outcome, with an overall survival of approximately 90% in early stage. 1,2 Fifteen to 30 years after therapy, cumulative mortality due to all second primary cancers exceeds deaths resulting from HL. Breast cancer (BC) represents the highest absolute risk of second cancers among HL survivors. 3–6 It is widely accepted that HL is extremely sensitive to radiotherapy (RT). In early stage, involved field RT (IF-RT) with 20 Gray (Gy) in combination with first-line chemotherapy consisting of Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD regimen) is a gold standard for disease treatment. Considering the young age of most patients at diagnosis and their long survival time, greater attention has been focused on long-term treatment toxicity. RT can induce cardiovascular disease and compromise thyroid or lung function and, above all, can lead to the development of secondary tumors. 2,7,8 Secondary malignancies are the leading cause of death in patients with a history of HL, with an 8-fold increased risk of BC. 3,9,10 Lately, it has been hypothesized that magnetic resonance imaging (MRI) characteristics of normal breast tissue may provide more precise BC risk information than mammographic density. Normal breast fibroglandular tissue on MRI may increase to variable levels after gadolinium administration; this has been termed background parenchymal enhancement (BPE). 11–14 BPE resulting from dynamic contrast-enhanced MRI has recently been shown to correlate with BC risk. BPE refers to the increase in normal-appearing fibroglandular tissue and is evaluated on the contrast-enhanced image at the first time point after contrast medium injection. BPE refers to the vascularity of the breast parenchymal tissue and varies with hormonal changes; in fact it changes with the menstrual cycle, increases with hormone replacement therapy and decreases with bilateral salpingo-oopherectomy, menopause and anti-estrogenic therapies. 15–18 The BRCA 1 and BRCA 2 genes are involved in DNA repair and cell cycle checkpoint control and are considered as tumor suppressor genes. The risk of developing BC is approximately 85% in BRCA 1 mutation carriers and approximately 45% in BRCA 2 mutation carriers. Therefore, the advice of the American Cancer Society is to carry out annual screening with breast MRI, starting from the age of 30, in all BRCA mutation carriers. 12,19,20 Here we perform a prospective study to evaluate the toxic effects of RT and the risk of developing BC in long-surviving patients from HL, comparing with age matched women who underwent screening breast MRI for high risk (BRCA1 and BRCA2 carriers). Patients and methods This prospective study focused on 62 women, aged between 22 and 49 years (median 35 years), with a history of previous early stage HL, treated with chemotherapy and RT for at least 15 years before (range 15–18 years ) and compared with 62 age-matched women with no previous history of cancer (control group) high risk for BC with BRCA1 or BRCA2 mutations carriers All patients were treated with 4 cycles of ABVD and chest-involved field RT All premenopausal women underwent clinical examination, bilateral digital breast tomosynthesis (DBT), breast ultrasound and MRI examination. All MRI examinations were performed in the second week of menstrual cycle. Written informed consent was obtained from all patients according to the Declaration of Helsinki principles. Magnetic resonance imaging protocol MRI examinations were performed on a 1.5 T MRI device (Achieva, Philips Medical Systems, Best, The Netherlands) by using a 16-channel breast coil. The following protocol was used: Transverse short TI inversion recovery (STIR) turbo-spin-echo (TSE) sequence (TR/TE/TI = 3.800/60/165 ms, field of view (FOV) = 250 × 450 mm (AP × RL), matrix 168 × 300, 50 slices, 3-mm slice thickness without gaps, 3 averages, turbo factor 23, resulting in a voxel size of 1.5 × 1.5 × 3.0 mm3); Transverse T2-weighted TSE (TR/TE = 6.300/130 ms, FOV = 250 × 450 mm (AP × RL), matrix 336 × 600, 50 slices, 3-mm slice thickness without gaps, 3 averages, turbo factor 59, SENSE factor 1.7, resulting in a voxel size of 0.75 × 0.75× 3.0 mm3); Three-dimensional (3D) dynamic, contrast-enhanced (CE) T1-weighted high resolution isotropic volume (THRIVE) sequences (TR/TE = 4.4/2.0 ms, FOV = 250 × 450 × 150 mm (AP × RL × FH), matrix 168 × 300, 100 slices, 1.5-mm slice thickness, turbo factor 50, SENSE factor 1.6, 6 dynamic acquisitions, 1.5-mm3 isotropic voxels, a dynamic data acquisition time of 1 min 30 s, and a total sequence duration of 9 min). Gadobutrol (Gadovist, Bayer, Berlin, Germany) was intravenously injected at a dose of 0.1 mmol/kg of body weight and flow rate of 1.5 ml/s followed by 20 ml of saline solution. Image subtraction sequences were created in order to diagnose all enhancing lesions. Image Analysis All MRI data were analysed on a diagnostic workstation equipped with dedicated software for MRI examination (View-ForumR5.1 V1L1 2006). Two radiologists with more than 5 years of experience in the field of breast MR blinded to the patient history and to clinical, DBT and ultrasound findings evaluated all subtracted and 3D Maximum Intensity Projection (MIP) MR enhanced images for classifying normal BPE. The third dynamic sequence (about after 3 minutes from the intravenous injection of contrast material) was used at this purpose as standard protocol. BPE was classified into four categories: minimal or 1 ( 75%) (Fig. 1 ). In case of suspected MRI lesions, BPE was assessed on the contralateral breast in order to avoid any confounding effect7. The post-processing mean duration time was of about 10 minutes for MR post-contrast imaging. Statistical Analysis Patients characteristics were assessed with summary statistics for the two groups. A t test for independent samples was used in order to compare differences in age and BPE type distribution in the two group of patients. The distribution of BPE patterns within the two groups of patients was calculated and the χ2 test was used in order to evaluate the significance of BPE type distribution in each group. A multivariate regression analysis including patient age at the time of breast MRI, age at the time of RT and years from RT was used searching for any confounding effect to BPE measurement and distribution among the case group. Cohen's kappa statistics was used in order to assess inter-observer agreement for classifying BPE. A k value of more than 0.81 was considered as almost perfect agreement and values of 0.61–0.80 and 0.41–0.60 respectively as substantial and moderate agreement. All calculations were performed using NCSS2007® statistical software. Results In HL survivors group, 13/62 cases of type 1 BPE (21%) were found, 18/62 of type 2 BPE (29%), 16/62 of type 3 BPE (26%), 15/62 of type 4 BPE (24%). Three patients of this group were affected by malignant lesions, two of these (ductal carcinoma in situ-DCIS, n = 1; non-special type-NST, n = 1) showed moderate BPE (Fig. 2 ) in contralateral breast and one (NST) marked BPE. Among the control group 12/62 women presented type 1 BPE (20%), 20/62 type 2 BPE (32%), 15/62 type 3 BPE (24%), 15/62 type 4 BPE (24%). The t test for independent samples showed no significant difference in age (p = 0.48) and BPE type distribution (p = 0.91) between the two groups of patients. The χ2 test demonstrated no significant difference in the distribution of the BPE types in both groups of patients (p = 0.98) with only a trend toward a prevalence of type 2 BPE in two groups (Table 1 ). Table 1 Distribution of the BPE types in HL survivors and age-matched control group. BPE1 BPE2 BPE3 BPE4 P value HL SURVIVORS 13 (21%) 18 (29%) 16 (26%) 15 (24%) P = 0.98 CONTROL 12 (19%) 20 (32%) 15 (24%) 15 (24%) The mean age at the time of chest RT was 19.16 years ± 7.65 (range 8–36) while the mean interval time from RT was 15.88 ± 6.66 (range 8–33). Multivariate regression analysis found no statistical significant effect of age, age at the time of treatment and years from treatment on BPE distribution (p = 0.17; coefficient of determination R2 = 0.08; multiple correlation coefficient = 0.28). For the single independent variables, the following values were found: age (p = 0.22; coefficient= -0.07); age at the time of treatment (p = 0.11; coefficient = 0.1); years from treatment (p = 0.35; coefficient = 0.06) (Table 2 ). Table 2 Multivariate regression analysis on BPE distribution between HL survivors and age-matched control group. mean standard dev. R p multivariate regression Age 35.56 7.56 -0.07 0.22 R2 = 0.08 p = 0.17 Age at treatment 19.16 7.65 0.1 0.11 Years from treatment 15.88 6.66 0.06 0.35 R: coefficient of determination for the single independent variables. R2: coefficient of determination for the multivariate regression analysis The inter-rater agreement in evaluating BPE patterns on MRI was almost perfect with Cohen’s k = 0.84. Discussion Treatment outcomes for early-stage HL have improved dramatically over the past few decades, and we have now reached a point where the problems of life after treatment have become almost more urgent than the treatment itself. Common late effects include second cancer, cardiovascular diseases, thyroid dysfunction, premature menopause, and fatigue. These late treatment sequelae can negatively affect survivor’s health and predispose to premature death. 1,7,8,21,22 Death in the first ten years after diagnosis is largely attributable to HL. With extended follow-up beyond ten years, treatment complications, predominantly secondary cancers and cardiovascular disease, emerge as leading causes of excess death and exhibit novel sex relationships in this young cohort. 1,2,4 Despite the development of numerous new directly targeted agents for the treatment of HL, the role of RT remains debated. Therefore, the current strategy in RT planning focuses on reducing the size of the irradiated fields; It is currently recognized that regional therapy alone is as effective as extended field RT but less toxic. In long-term HL survivors, the most common secondary tumors are BC in females and lung cancer in male patients. Furthermore, women treated with RT for HL have a higher risk of developing BC compared to the general population. 3,5,23–25 Systematic lifelong follow-up is needed to examine the emergence of long-term toxicity and associated morbidity and mortality. Specialized follow-up with breast screening is recommended for women at high risk of secondary BC in order to detect them early and to optimize their management. 13,14,26 According to consensus guidelines there are recommendations for annual risk-based BC surveillance with mammography or breast MRI or a combination of mammography and MRI for women exposed to chest radiation, beginning 8 years or more after exposure. 4,13,14,20,23,27 Variable risk estimations have been reported; however, the age at HL treatment seems to be the most important risk factor. The greatest risk has been described in case of women treated around puberty probably due to the increased sensitivity of the breast tissue to the radiation effect during this period of high proliferation. 4,24 Secondary BC in HL survivors usually occur at least 20 years before as compared with that of sporadic cancers, with a median age of approximately 40 years at the time of diagnosis. These cancers were reported to be often bilateral, often on the margins of RT field and located on external quadrants of the breast. 4–6,23–25,28 An association between BPE and BC risk has been proposed as well as its potential use as an imaging biomarker. On the other side, the sensitivity of MRI imaging significantly decreases in women with moderate and marked BPE as compared with women with minimal and mild BPE due to the reduction of contrast resolution on enhanced MRI. 11,12,19 Zeng et al found that BPE on screening breast MRI in patients who have previously had RT for HL is significantly higher than in matched controls. They reported a positive correlation between BPE and age in the case group and a negative correlation between BPE and age in the control group. Therefore, increased BPE after RT compared to other high-risk women in the control group suggested a very high risk of BC in HL patients. This data might be caused by long-term effects of radiation damage to microvasculature, probably a chronic inflammatory response. 29 In this study we found that BPE in log-survival chest radiotreated HL women was comparable to that of healthy BRCA carriers woman; we found 31 cases (50%) of moderate and marked BPE in the HL survivors group and 30 (48%) in the BRCA carrier control group. In the long-survival HL group, 3 (5%) malignant lesions were found, two of these (ductal carcinoma in situ-DCIS, n = 1; non-special type-NST, n = 1) had moderate BPE lesions in the contralateral breast and one (NST) marked BPE. Since MRI is indicated in women at high risk of BC, defined as a lifetime risk greater than 20–25% (as determined by genetic factors or a risk model including family history), most studies on BPE they were performed only in high-risk women. However, two studies have analyzed the use of BPE to predict the onset of BC in women at average risk: one study demonstrated a positive correlation between BPE and BC while the other study found no correlation. A limitation of these studies was that breast MRI was performed in women with symptoms such as bloody nipple discharge or in women already diagnosed with cancer; therefore, it is uncertain whether the findings of these studies would extend to asymptomatic women with an average lifetime risk of BC. 11,12,19,29,30 BPE reflects varying levels of physiologic enhancement of normal fibroglandular tissue and has recently become a highly studied imaging indicator of BC risk and treatment outcomes. Recent data has shown that higher levels of BPE may make the breast tissue environment more likely to develop BC. 11,30,31 The carcinogenesis pathway could not be related to an increase of BPE or microvasculature injury but mostly based on a genetic damage. In fact, the underlying mechanisms of radiation-induced carcinogenesis are not fully known, although the mutagen effect of ionizing radiations has long been reported. 32 A better assessment of BC risk, especially with the arrival of new targeted therapies, will allow the most appropriate therapy to be chosen, reducing the risk of second tumors. 33,34 In conclusion, long-survival HL have an increased incidence of BC than in the general population, and in our study, the analysis of BPE was comparable to healthy women at high risk for BC with BRCA mutation carriers. Future research should be directed at examining the underlying cancer biology and genetic susceptibility of treatment-induced tumors. Declarations All authors declare no conflict of interest. CRediT authorship contribution statement MM, MT and FG conceived and designed the study. MPC, BT, AS, AF, MM, CG and MT acquired the data. MT, MM, CG and FG analysed and interpreted the data. FEL, MT, MM and FG drafted the manuscript. All authors revised the manuscript. All authors read and approved the final manuscript. Human Ethics and Consent to Participate declarations : Institutional Review Board Statement: This study was conducted in accordance with the Declaration of Helsinki. Ethical review and approval were waived for this study: since the study data were collected during routine clinical activity and fully anonymized, a formal institutional review board approval was exempted. Informed Consent Statement: Each patient enrolled in this study was informed about the procedures and signed consent to allow data collection and analysis for research purposes. Data Availability Statement The relevant data have been included in the manuscript. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Funding All authors declare no funding. References Gaudio F, Giordano A, Pavone V, et al. 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Background parenchymal enhancement and breast cancer: a review of the emerging evidences about its potential use as imaging biomarker. Br J Radiol . 2021;94(1119):20200630. doi:10.1259/bjr.20200630 Giess CS, Yeh ED, Raza S, Birdwell RL. Background Parenchymal Enhancement at Breast MR Imaging: Normal Patterns, Diagnostic Challenges, and Potential for False-Positive and False-Negative Interpretation. RadioGraphics . 2014;34(1):234-247. doi:10.1148/rg.341135034 Allan JM, Travis LB. Mechanisms of therapy-related carcinogenesis. Nat Rev Cancer . 2005;5(12):943-955. doi:10.1038/nrc1749 Cheson BD, Bartlett NL, LaPlant B, et al. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Lancet Haematol . 2020;7(11):e808-e815. doi:10.1016/S2352-3026(20)30275-1 Bröckelmann PJ, Goergen H, Keller U, et al. Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma. JAMA Oncol . 2020;6(6):872. doi:10.1001/jamaoncol.2020.0750 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4427101","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":309184016,"identity":"88d4c039-acb0-4d70-8a31-4ef9bd9d248e","order_by":0,"name":"Filomena Emanuela Laddaga","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Filomena","middleName":"Emanuela","lastName":"Laddaga","suffix":""},{"id":309184017,"identity":"a45f8773-6b82-48d7-b35d-c14fd8353de1","order_by":1,"name":"Michele Telegrafo","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Michele","middleName":"","lastName":"Telegrafo","suffix":""},{"id":309184018,"identity":"48f4e703-4a31-4869-aab5-6b5574babf6f","order_by":2,"name":"Carmela Garzillo","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Carmela","middleName":"","lastName":"Garzillo","suffix":""},{"id":309184019,"identity":"452bd44e-bd25-4ff6-b12a-11b4c5114470","order_by":3,"name":"Maria Paola Ciliberti","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Paola","lastName":"Ciliberti","suffix":""},{"id":309184020,"identity":"d6cacb59-8858-40c9-9f26-aff63d95a1bb","order_by":4,"name":"Barbara Turi","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Turi","suffix":""},{"id":309184021,"identity":"88b677e5-5d59-4712-9599-0117c8c67e9a","order_by":5,"name":"Angela Sardaro","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Angela","middleName":"","lastName":"Sardaro","suffix":""},{"id":309184022,"identity":"2fb7161b-0a93-4989-8254-e5b5b906b9f7","order_by":6,"name":"Alba Fiorentino","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Alba","middleName":"","lastName":"Fiorentino","suffix":""},{"id":309184023,"identity":"880fa88b-4b84-4c31-8970-76debd57096c","order_by":7,"name":"Marco Moschetta","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Moschetta","suffix":""},{"id":309184024,"identity":"2f03d943-09c7-417e-b9fb-55ba2908ea10","order_by":8,"name":"Francesco Gaudio","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYBAC9gYwxcwDZDEeSAAy2Qhp4TkA0wJkQbQQ0gPTwsAgkcAAYRPUIn348YufbdYy/JKPHxx4UGPDwCffQEALX5qZZW9bOo/k7DSDAwnH0gg7zJ6HwcyAt+0wj8HtBIMDiQ2HifALD/s3w78gLTePfwBq+U+MFh7jx2BbbvCAbDlAlJYyZplzQL/05BQA/ZLMw8aWQNBhmz++KbO252c/vvHhjxo7OfnmAwSsAcaDBIoZBNUDAfMHYlSNglEwCkbBCAYAlco8v0WyYI8AAAAASUVORK5CYII=","orcid":"","institution":"LUM Jean Monnet University","correspondingAuthor":true,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Gaudio","suffix":""}],"badges":[],"createdAt":"2024-05-15 19:48:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4427101/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4427101/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57874293,"identity":"255c92d2-67b6-4dc9-81e7-413150678af4","added_by":"auto","created_at":"2024-06-06 18:45:47","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":67538,"visible":true,"origin":"","legend":"\u003cp\u003e3D Maximum Intensity Projection (MIP) MR enhanced images.: BPE classification: A. Type 1- Minimal. B. Type 2-Mild. C. Type 3-Moderate. D.Type 4-Marked.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4427101/v1/9d5d37986217fb63daa5dfd8.jpg"},{"id":57874294,"identity":"00c8a80d-59d9-48f4-b851-eed4207a1a2d","added_by":"auto","created_at":"2024-06-06 18:45:47","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":41898,"visible":true,"origin":"","legend":"\u003cp\u003eSubtracted THRIVE (A) and 3D MIP (B) contrast enhanced MRI showing a NST breast cancer on the left side in a 44-year-old HL with type 3 BPE evaluated in the contralateral breast\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4427101/v1/c17dbfb2fd4b1389c8692c96.jpg"},{"id":58298639,"identity":"ade0c29f-1b87-445a-8780-d81ae5122678","added_by":"auto","created_at":"2024-06-13 15:27:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":520873,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4427101/v1/5c56d203-0cb6-4ef1-b792-8710684f1af7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eComparison of Breast Parenchyma in Chest Radiotreated Survivors of Hodgkin's Lymphoma and Healthy Women with Brca Mutation Carriers: A Case Control Study\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCurrently, Hodgkin lymphoma (HL) has an excellent clinical outcome, with an overall survival of approximately 90% in early stage.\u003csup\u003e1,2\u003c/sup\u003e Fifteen to 30 years after therapy, cumulative mortality due to all second primary cancers exceeds deaths resulting from HL. Breast cancer (BC) represents the highest absolute risk of second cancers among HL survivors.\u003csup\u003e3\u0026ndash;6\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIt is widely accepted that HL is extremely sensitive to radiotherapy (RT). In early stage, involved field RT (IF-RT) with 20 Gray (Gy) in combination with first-line chemotherapy consisting of Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD regimen) is a gold standard for disease treatment. Considering the young age of most patients at diagnosis and their long survival time, greater attention has been focused on long-term treatment toxicity. RT can induce cardiovascular disease and compromise thyroid or lung function and, above all, can lead to the development of secondary tumors.\u003csup\u003e2,7,8\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSecondary malignancies are the leading cause of death in patients with a history of HL, with an 8-fold increased risk of BC.\u003csup\u003e3,9,10\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eLately, it has been hypothesized that magnetic resonance imaging (MRI) characteristics of normal breast tissue may provide more precise BC risk information than mammographic density. Normal breast fibroglandular tissue on MRI may increase to variable levels after gadolinium administration; this has been termed background parenchymal enhancement (BPE).\u003csup\u003e11\u0026ndash;14\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBPE resulting from dynamic contrast-enhanced MRI has recently been shown to correlate with BC risk. BPE refers to the increase in normal-appearing fibroglandular tissue and is evaluated on the contrast-enhanced image at the first time point after contrast medium injection. BPE refers to the vascularity of the breast parenchymal tissue and varies with hormonal changes; in fact it changes with the menstrual cycle, increases with hormone replacement therapy and decreases with bilateral salpingo-oopherectomy, menopause and anti-estrogenic therapies.\u003csup\u003e15\u0026ndash;18\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe BRCA 1 and BRCA 2 genes are involved in DNA repair and cell cycle checkpoint control and are considered as tumor suppressor genes. The risk of developing BC is approximately 85% in BRCA 1 mutation carriers and approximately 45% in BRCA 2 mutation carriers. Therefore, the advice of the American Cancer Society is to carry out annual screening with breast MRI, starting from the age of 30, in all BRCA mutation carriers.\u003csup\u003e12,19,20\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHere we perform a prospective study to evaluate the toxic effects of RT and the risk of developing BC in long-surviving patients from HL, comparing with age matched women who underwent screening breast MRI for high risk (BRCA1 and BRCA2 carriers).\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eThis prospective study focused on 62 women, aged between 22 and 49 years (median 35 years), with a history of previous early stage HL, treated with chemotherapy and RT for at least 15 years before (range 15\u0026ndash;18 years ) and compared with 62 age-matched women with no previous history of cancer (control group) high risk for BC with BRCA1 or BRCA2 mutations carriers\u003c/p\u003e \u003cp\u003eAll patients were treated with 4 cycles of ABVD and chest-involved field RT\u003c/p\u003e \u003cp\u003eAll premenopausal women underwent clinical examination, bilateral digital breast tomosynthesis (DBT), breast ultrasound and MRI examination.\u003c/p\u003e \u003cp\u003eAll MRI examinations were performed in the second week of menstrual cycle.\u003c/p\u003e \u003cp\u003e Written informed consent was obtained from all patients according to the Declaration of Helsinki principles.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMagnetic resonance imaging protocol\u003c/h2\u003e \u003cp\u003eMRI examinations were performed on a 1.5 T MRI device (Achieva, Philips Medical Systems, Best, The Netherlands) by using a 16-channel breast coil. The following protocol was used:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eTransverse short TI inversion recovery (STIR) turbo-spin-echo (TSE) sequence (TR/TE/TI\u0026thinsp;=\u0026thinsp;3.800/60/165 ms, field of view (FOV)\u0026thinsp;=\u0026thinsp;250 \u0026times; 450 mm (AP \u0026times; RL), matrix 168 \u0026times; 300, 50 slices, 3-mm slice thickness without gaps, 3 averages, turbo factor 23, resulting in a voxel size of 1.5 \u0026times; 1.5 \u0026times; 3.0 mm3);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTransverse T2-weighted TSE (TR/TE\u0026thinsp;=\u0026thinsp;6.300/130 ms, FOV\u0026thinsp;=\u0026thinsp;250 \u0026times; 450 mm (AP \u0026times; RL), matrix 336 \u0026times; 600, 50 slices, 3-mm slice thickness without gaps, 3 averages, turbo factor 59, SENSE factor 1.7, resulting in a voxel size of 0.75 \u0026times; 0.75\u0026times; 3.0 mm3);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThree-dimensional (3D) dynamic, contrast-enhanced (CE) T1-weighted high resolution isotropic volume (THRIVE) sequences (TR/TE\u0026thinsp;=\u0026thinsp;4.4/2.0 ms, FOV\u0026thinsp;=\u0026thinsp;250 \u0026times; 450 \u0026times; 150 mm (AP \u0026times; RL \u0026times; FH), matrix 168 \u0026times; 300, 100 slices, 1.5-mm slice thickness, turbo factor 50, SENSE factor 1.6, 6 dynamic acquisitions, 1.5-mm3 isotropic voxels, a dynamic data acquisition time of 1 min 30 s, and a total sequence duration of 9 min). Gadobutrol (Gadovist, Bayer, Berlin, Germany) was intravenously injected at a dose of 0.1 mmol/kg of body weight and flow rate of 1.5 ml/s followed by 20 ml of saline solution. Image subtraction sequences were created in order to diagnose all enhancing lesions.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eImage Analysis\u003c/h2\u003e \u003cp\u003eAll MRI data were analysed on a diagnostic workstation equipped with dedicated software for MRI examination (View-ForumR5.1 V1L1 2006). Two radiologists with more than 5 years of experience in the field of breast MR blinded to the patient history and to clinical, DBT and ultrasound findings evaluated all subtracted and 3D Maximum Intensity Projection (MIP) MR enhanced images for classifying normal BPE. The third dynamic sequence (about after 3 minutes from the intravenous injection of contrast material) was used at this purpose as standard protocol. BPE was classified into four categories: minimal or 1 (\u0026lt;\u0026thinsp;25% of glandular tissue enhancement), mild or 2 (25\u0026ndash;50% enhancement), moderate or 3 (50\u0026ndash;75% enhancement) and marked or 4 (\u0026gt;\u0026thinsp;75%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In case of suspected MRI lesions, BPE was assessed on the contralateral breast in order to avoid any confounding effect7. The post-processing mean duration time was of about 10 minutes for MR post-contrast imaging.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003ePatients characteristics were assessed with summary statistics for the two groups. A \u003cem\u003et\u003c/em\u003e test for independent samples was used in order to compare differences in age and BPE type distribution in the two group of patients.\u003c/p\u003e \u003cp\u003eThe distribution of BPE patterns within the two groups of patients was calculated and the χ2 test was used in order to evaluate the significance of BPE type distribution in each group. A multivariate regression analysis including patient age at the time of breast MRI, age at the time of RT and years from RT was used searching for any confounding effect to BPE measurement and distribution among the case group. Cohen's kappa statistics was used in order to assess inter-observer agreement for classifying BPE. A k value of more than 0.81 was considered as almost perfect agreement and values of 0.61\u0026ndash;0.80 and 0.41\u0026ndash;0.60 respectively as substantial and moderate agreement.\u003c/p\u003e \u003cp\u003eAll calculations were performed using NCSS2007\u0026reg; statistical software.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn HL survivors group, 13/62 cases of type 1 BPE (21%) were found, 18/62 of type 2 BPE (29%), 16/62 of type 3 BPE (26%), 15/62 of type 4 BPE (24%). Three patients of this group were affected by malignant lesions, two of these (ductal carcinoma in situ-DCIS, n\u0026thinsp;=\u0026thinsp;1; non-special type-NST, n\u0026thinsp;=\u0026thinsp;1) showed moderate BPE (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) in contralateral breast and one (NST) marked BPE. Among the control group 12/62 women presented type 1 BPE (20%), 20/62 type 2 BPE (32%), 15/62 type 3 BPE (24%), 15/62 type 4 BPE (24%).\u003c/p\u003e \u003cp\u003eThe \u003cem\u003et\u003c/em\u003e test for independent samples showed no significant difference in age (p\u0026thinsp;=\u0026thinsp;0.48) and BPE type distribution (p\u0026thinsp;=\u0026thinsp;0.91) between the two groups of patients. The χ2 test demonstrated no significant difference in the distribution of the BPE types in both groups of patients (p\u0026thinsp;=\u0026thinsp;0.98) with only a trend toward a prevalence of type 2 BPE in two groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of the BPE types in HL survivors and age-matched control group.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBPE1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBPE2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBPE3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBPE4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHL SURVIVORS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCONTROL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (24%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe mean age at the time of chest RT was 19.16 years\u0026thinsp;\u0026plusmn;\u0026thinsp;7.65 (range 8\u0026ndash;36) while the\u003c/p\u003e \u003cp\u003emean interval time from RT was 15.88\u0026thinsp;\u0026plusmn;\u0026thinsp;6.66 (range 8\u0026ndash;33).\u003c/p\u003e \u003cp\u003eMultivariate regression analysis found no statistical significant effect of age, age at the time of treatment and years from treatment on BPE distribution (p\u0026thinsp;=\u0026thinsp;0.17; coefficient of determination R2\u0026thinsp;=\u0026thinsp;0.08; multiple correlation coefficient\u0026thinsp;=\u0026thinsp;0.28). For the single independent variables, the following values were found: age (p\u0026thinsp;=\u0026thinsp;0.22; coefficient= -0.07); age at the time of treatment (p\u0026thinsp;=\u0026thinsp;0.11; coefficient\u0026thinsp;=\u0026thinsp;0.1); years from treatment (p\u0026thinsp;=\u0026thinsp;0.35; coefficient\u0026thinsp;=\u0026thinsp;0.06) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate regression analysis on BPE distribution between HL survivors and age-matched control group.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003emean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003estandard dev.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003emultivariate\u003c/p\u003e \u003cp\u003eregression\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eR2\u0026thinsp;=\u0026thinsp;0.08\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at\u003c/p\u003e \u003cp\u003etreatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYears from\u003c/p\u003e \u003cp\u003etreatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eR: coefficient of determination for the single independent variables. R2: coefficient of determination for the multivariate regression analysis\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe inter-rater agreement in evaluating BPE patterns on MRI was almost perfect with Cohen\u0026rsquo;s k\u0026thinsp;=\u0026thinsp;0.84.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTreatment outcomes for early-stage HL have improved dramatically over the past few decades, and we have now reached a point where the problems of life after treatment have become almost more urgent than the treatment itself. Common late effects include second cancer, cardiovascular diseases, thyroid dysfunction, premature menopause, and fatigue. These late treatment sequelae can negatively affect survivor\u0026rsquo;s health and predispose to premature death.\u003csup\u003e1,7,8,21,22\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDeath in the first ten years after diagnosis is largely attributable to HL. With extended follow-up beyond ten years, treatment complications, predominantly secondary cancers and cardiovascular disease, emerge as leading causes of excess death and exhibit novel sex relationships in this young cohort.\u003csup\u003e1,2,4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDespite the development of numerous new directly targeted agents for the treatment of HL, the role of RT remains debated. Therefore, the current strategy in RT planning focuses on reducing the size of the irradiated fields; It is currently recognized that regional therapy alone is as effective as extended field RT but less toxic.\u003c/p\u003e \u003cp\u003eIn long-term HL survivors, the most common secondary tumors are BC in females and lung cancer in male patients. Furthermore, women treated with RT for HL have a higher risk of developing BC compared to the general population.\u003csup\u003e3,5,23\u0026ndash;25\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSystematic lifelong follow-up is needed to examine the emergence of long-term toxicity and associated morbidity and mortality.\u003c/p\u003e \u003cp\u003eSpecialized follow-up with breast screening is recommended for women at high risk of secondary BC in order to detect them early and to optimize their management.\u003csup\u003e13,14,26\u003c/sup\u003e According to consensus guidelines there are recommendations for annual risk-based BC surveillance with mammography or breast MRI or a combination of mammography and MRI for women exposed to chest radiation, beginning 8 years or more after exposure.\u003csup\u003e4,13,14,20,23,27\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eVariable risk estimations have been reported; however, the age at HL treatment seems to be the most important risk factor. The greatest risk has been described in case of women treated around puberty probably due to the increased sensitivity of the breast tissue to the radiation effect during this period of high proliferation.\u003csup\u003e4,24\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSecondary BC in HL survivors usually occur at least 20 years before as compared with that of sporadic cancers, with a median age of approximately 40 years at the time of diagnosis. These cancers were reported to be often bilateral, often on the margins of RT field and located on external quadrants of the breast.\u003csup\u003e4\u0026ndash;6,23\u0026ndash;25,28\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAn association between BPE and BC risk has been proposed as well as its potential use as an imaging biomarker. On the other side, the sensitivity of MRI imaging significantly decreases in women with moderate and marked BPE as compared with women with minimal and mild BPE due to the reduction of contrast resolution on enhanced MRI.\u003csup\u003e11,12,19\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eZeng et al found that BPE on screening breast MRI in patients who have previously had RT for HL is significantly higher than in matched controls. They reported a positive correlation between BPE and age in the case group and a negative correlation between BPE and age in the control group. Therefore, increased BPE after RT compared to other high-risk women in the control group suggested a very high risk of BC in HL patients. This data might be caused by long-term effects of radiation damage to microvasculature, probably a chronic inflammatory response. \u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this study we found that BPE in log-survival chest radiotreated HL women was comparable to that of healthy BRCA carriers woman; we found 31 cases (50%) of moderate and marked BPE in the HL survivors group and 30 (48%) in the BRCA carrier control group. In the long-survival HL group, 3 (5%) malignant lesions were found, two of these (ductal carcinoma in situ-DCIS, n\u0026thinsp;=\u0026thinsp;1; non-special type-NST, n\u0026thinsp;=\u0026thinsp;1) had moderate BPE lesions in the contralateral breast and one (NST) marked BPE.\u003c/p\u003e \u003cp\u003eSince MRI is indicated in women at high risk of BC, defined as a lifetime risk greater than 20\u0026ndash;25% (as determined by genetic factors or a risk model including family history), most studies on BPE they were performed only in high-risk women. However, two studies have analyzed the use of BPE to predict the onset of BC in women at average risk: one study demonstrated a positive correlation between BPE and BC while the other study found no correlation. A limitation of these studies was that breast MRI was performed in women with symptoms such as bloody nipple discharge or in women already diagnosed with cancer; therefore, it is uncertain whether the findings of these studies would extend to asymptomatic women with an average lifetime risk of BC.\u003csup\u003e11,12,19,29,30\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBPE reflects varying levels of physiologic enhancement of normal fibroglandular tissue and has recently become a highly studied imaging indicator of BC risk and treatment outcomes. Recent data has shown that higher levels of BPE may make the breast tissue environment more likely to develop BC.\u003csup\u003e11,30,31\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe carcinogenesis pathway could not be related to an increase of BPE or microvasculature injury but mostly based on a genetic damage. In fact, the underlying mechanisms of radiation-induced carcinogenesis are not fully known, although the mutagen effect of ionizing radiations has long been reported.\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA better assessment of BC risk, especially with the arrival of new targeted therapies, will allow the most appropriate therapy to be chosen, reducing the risk of second tumors.\u003csup\u003e33,34\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn conclusion, long-survival HL have an increased incidence of BC than in the general population, and in our study, the analysis of BPE was comparable to healthy women at high risk for BC with BRCA mutation carriers. Future research should be directed at examining the underlying cancer biology and genetic susceptibility of treatment-induced tumors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAll authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMM, MT and FG conceived and designed the study. MPC, BT, AS, AF, MM, CG and MT acquired the data. MT, MM, CG and FG analysed and interpreted the data. FEL, MT, MM and FG drafted the manuscript. All authors revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThis study was conducted in accordance with the Declaration of Helsinki. Ethical review and approval were waived for this study: since the study data were collected during routine clinical activity and fully anonymized, a formal institutional review board approval was exempted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInformed Consent Statement:\u003c/em\u003e\u003c/strong\u003eEach patient enrolled in this study was informed about the procedures and signed consent to allow data collection and analysis for research purposes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe relevant data have been included in the manuscript. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no funding.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGaudio F, Giordano A, Pavone V, et al. Outcome of very late relapse in patients with Hodgkin\u0026rsquo;s lymphomas. \u003cem\u003eAdv Hematol\u003c/em\u003e. 2011;2011. doi:10.1155/2011/707542\u003c/li\u003e\n\u003cli\u003eLaddaga FE, Moschetta M, Perrone T, et al. Long-term Hodgkin Lymphoma Survivors: A Glimpse of What Happens 10 Years After Treatment. \u003cem\u003eClin Lymphoma Myeloma Leuk\u003c/em\u003e. 2020;20(8):e506-e512. doi:10.1016/j.clml.2020.03.006\u003c/li\u003e\n\u003cli\u003eTravis LB, Hill DA, Dores GM, et al. Breast Cancer Following Radiotherapy and Chemotherapy Among Young Women With Hodgkin Disease. \u003cem\u003eJAMA\u003c/em\u003e. 2003;290(4):465. doi:10.1001/jama.290.4.465\u003c/li\u003e\n\u003cli\u003eSud A, Thomsen H, Sundquist K, Houlston RS, Hemminki K. Risk of Second Cancer in Hodgkin Lymphoma Survivors and Influence of Family History. \u003cem\u003eJournal of Clinical Oncology\u003c/em\u003e. 2017;35(14):1584-1590. doi:10.1200/JCO.2016.70.9709\u003c/li\u003e\n\u003cli\u003eIbrahim EM, Abouelkhair KM, Kazkaz GA, Elmasri OA, Al-Foheidi M. Risk of second breast cancer in female Hodgkin\u0026rsquo;s lymphoma survivors: a meta-analysis. \u003cem\u003eBMC Cancer\u003c/em\u003e. 2012;12(1):197. doi:10.1186/1471-2407-12-197\u003c/li\u003e\n\u003cli\u003evan Leeuwen FE, Ng AK. Long-term risk of second malignancy and cardiovascular disease after Hodgkin lymphoma treatment. \u003cem\u003eHematology\u003c/em\u003e. 2016;2016(1):323-330. doi:10.1182/asheducation-2016.1.323\u003c/li\u003e\n\u003cli\u003eGaudio F, Nardelli C, Masciandaro P, et al. Pregnancy rate and outcome of pregnancies in long-term survivors of Hodgkin\u0026rsquo;s lymphoma. \u003cem\u003eAnn Hematol\u003c/em\u003e. 2019;98(8). doi:10.1007/s00277-019-03684-0\u003c/li\u003e\n\u003cli\u003eLaddaga FE, Masciopinto P, Nardelli C, et al. In male Hodgkin lymphoma patients, impaired fertility may be improved by non-gonadotoxic therapy. \u003cem\u003eBr J Haematol\u003c/em\u003e. 2022;196(1):110-115. doi:10.1111/bjh.17767\u003c/li\u003e\n\u003cli\u003eElkin EB, Klem ML, Gonzales AM, et al. 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Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma. \u003cem\u003eJAMA Oncol\u003c/em\u003e. 2020;6(6):872. doi:10.1001/jamaoncol.2020.0750\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hodgkin, long term survivors, late toxicity, radiotherapy, Breast cancer","lastPublishedDoi":"10.21203/rs.3.rs-4427101/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4427101/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIncreased background parenchymal enhancement (BPE) is an imaging biomarker of higher risk of BC. The aim of this prospective study was to evaluate the distribution of BPE patterns and the possible onset of BC in long-term HL survivors treated with chemotherapy and RT and to compare them with age-matched women with BRCA mutation carriers and without a history of cancer.\u003c/p\u003e \u003cp\u003e62 women, long-term survivors of HL for at least 15 years and 62 consecutive women of the same age with BRCA mutation carriers, underwent screening with dynamic contrast magnetic resonance imaging. BPE was comparable in the two groups: 31 cases (50%) of moderate and marked BPE in the long-surviving HL group and 30 (48%) in the BRCA carrier control group. In the long-surviving HL group, 3 (5%) malignant lesions were found, two of these (ductal carcinoma in situ-DCIS, n\u0026thinsp;=\u0026thinsp;1; non-special type-NST, n\u0026thinsp;=\u0026thinsp;1) had moderate BPE lesions in the contralateral breast and one (NST ) marked BPE. We found a BPE comparable to healthy women at high risk for BC with BRCA mutation carriers. Future research should be directed at examining the underlying cancer biology and genetic susceptibility of treatment-induced tumors.\u003c/p\u003e","manuscriptTitle":"Comparison of Breast Parenchyma in Chest Radiotreated Survivors of Hodgkin's Lymphoma and Healthy Women with Brca Mutation Carriers: A Case Control Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-06 18:45:43","doi":"10.21203/rs.3.rs-4427101/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d7d0aded-8cba-429f-ba27-3aee8c00edb8","owner":[],"postedDate":"June 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-13T15:03:03+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-06 18:45:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4427101","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4427101","identity":"rs-4427101","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}