Publications by authors named "Erik Holmberg"

129 Publications

High PDGFRb Expression Predicts Resistance to Radiotherapy in DCIS within the SweDCIS Randomized Trial.

Clin Cancer Res 2021 May 5. Epub 2021 May 5.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Purpose: This study analyzes the potential of stromal platelet-derived growth factor receptor-beta (PDGFRb) expression as biomarker for radiotherapy (RT) benefit on ipsilateral breast events (IBE) in ductal carcinoma (DCIS). Improved identification of DCIS patients refractory to adjuvant whole-breast RT is needed. Predictive biomarker studies in DCIS have focused on tumor cell features rather than the tumor-associated stroma, despite growing evidence of its influence on therapy efficiency.

Methods: Samples from the Swedish randomized radiotherapy DCIS trial (SweDCIS) were subjected to IHC analysis for stromal PDGFRb expression. IBE incidence at 10 years after breast-conserving surgery was the primary endpoint. Interactions between marker and treatment were analyzed.

Results: PDGFRb score was predictive for RT benefit with regard to IBE ( = 0.002 and = 0.008 adjusted multivariably). Patients of the PDGFRb group had a strong benefit from RT regarding IBE risk [HR, 0.23; 95% confidence interval (CI), 0.12-0.45; < 0.001] with an absolute risk reduction of 21% (cumulative risk 7% vs. 28%) at 10 years. No significant risk reduction by RT was observed for patients of the PDGFRb group (HR, 0.83; 0.51-1.34; = 0.444; cumulative risk 22% vs. 25%). The RT response-predictive effect of stromal PDGFRb was equally strong in analyses for and invasive IBE when analyzed separately ( IBE: = 0.029; invasive IBE: = 0.044).

Conclusions: Results suggest high stromal PDGFRb expression as a novel biomarker identifying DCIS patients who are refractory to standard whole-breast adjuvant RT. The data imply previously unrecognized fibroblast-mediated modulation of radiosensitivity of DCIS, which should be further explored from mechanistic and targeting perspectives.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4300DOI Listing
May 2021

Increased risk for renal cell carcinoma in end stage renal disease - a population-based case-control study.

Scand J Urol 2021 Mar 26:1-6. Epub 2021 Mar 26.

Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Purpose: End-stage renal disease (ESRD) is a known risk factor for the development of renal cell carcinoma (RCC). This case-control study was performed to assess the risk in a nationwide cohort and evaluate tumor characteristics and survival in the ESRD-RCC population.

Methods: In this study, 9,299 patients with RCC identified in the National Swedish Kidney Cancer Register from 2005 until 2014 and 93,895 matched controls were linked to the Swedish Renal Registry and the National Patient Register. ESRD was defined as chronic kidney disease stage 5, kidney transplantation or kidney dialysis 0-40 years before the diagnosis of RCC.

Results: A total of 117 patients with ESRD and subsequent RCC were identified and compared with 9,087 patients with RCC. There was a 4.5-times increased risk for RCC among ESRD patients (95% CI = 3.6-5.6;  < 0.001) compared to matched controls. Longer time with ESRD increased the risk of RCC (ESRD > 9 years, OR = 10.2, 95% CI = 7.0-14.8). The ESRD-RCC patients were younger ( = 0.002), had smaller tumors ( < 0.001) and had lower tumor stage ( = 0.045). The incidence of papillary and chromophobe RCC was higher and clear cell RCC lower among the ESRD patients ( < 0.001). The 5-year overall survival was 50% in ESRD-RCC patients and 63% in RCC-only patients ( < 0.05).

Conclusion: More than 9 years with ESRD increased the risk of developing RCC 10-times compared to individuals without ESRD and the tumors showed a different histopathological pattern. Despite a less advanced tumor stage at diagnosis, the overall survival in ESRD-RCC patients was lower compared to patients with RCC-only.
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http://dx.doi.org/10.1080/21681805.2021.1900387DOI Listing
March 2021

Preoperative and intraoperative assessment of myometrial invasion in endometrial cancer - a Swedish Gynecologic Cancer Group (SweGCG) study.

Acta Obstet Gynecol Scand 2021 Mar 15. Epub 2021 Mar 15.

Department of Medical Oncology, Institute of Clinical Sciences, Lund University, Lund, Sweden.

Introduction: Deep myometrial invasion (≥50%) is a prognostic factor for lymph node metastases and decreased survival in endometrial cancer. There is no consensus regarding which pre/intraoperative diagnostic method should be preferred. Our aim was to explore the pattern of diagnostic methods for myometrial invasion assessment in Sweden and to evaluate differences among magnetic resonance imaging (MRI), transvaginal sonography, frozen section, and gross examination in clinical practice.

Material And Methods: This is a nationwide historical cohort study; women with endometrial cancer with data on assessment of myometrial invasion and FIGO stage I-III registered in the Swedish Quality Registry for Gynecologic Cancer (SQRGC) between 2017 and 2019 were eligible. Data on age, histology, FIGO stage, method and results of myometrial invasion assessment, pathology results, and hospital level were collected from the SQRGC. The final assessment by the pathologist was considered gold standard.

Results: In the study population of 1401 women, 32% (n=448) had a myometrial invasion ≥50%. The methods reported for myometrial invasion assessment were transvaginal sonography in 59%, MRI in 28%, gross examination in 8% and frozen section in 5% of cases. Only minor differences were found for age and FIGO stage when comparing methods applied for myometrial invasion assessment. The sensitivity, specificity, and accuracy to find myometrial invasion ≥50% with transvaginal sonography was 65.6%, 80.3% and 75.8%, for MRI 76.9%, 71.9% and 73.8%, for gross examination 71.9%, 93.6% and 87.3% while for frozen section it was 90.0%, 92.7% and 92.0% respectively.

Conclusions: In Sweden, the assessment of deep myometrial invasion is most often performed with transvaginal sonography, but the sensitivity is lower than for the other diagnostic methods. In clinical practice, the accuracy is moderate for transvaginal sonography and MRI.
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http://dx.doi.org/10.1111/aogs.14146DOI Listing
March 2021

Prognostic and predictive impact of stroma cells defined by PDGFRb expression in early breast cancer: results from the randomized SweBCG91RT trial.

Breast Cancer Res Treat 2021 May 4;187(1):45-55. Epub 2021 Mar 4.

Department of Oncology, Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Purpose: Predictive biomarkers are needed to aid the individualization of radiotherapy (RT) in breast cancer. Cancer-associated fibroblasts have been implicated in tumor radioresistance and can be identified by platelet-derived growth factor receptor-beta (PDGFRb). This study aims to analyze how PDGFRb expression affects RT benefit in a large randomized RT trial.

Methods: PDGFRb was assessed by immunohistochemistry on tissue microarrays from 989 tumors of the SweBCG91RT trial, which enrolled lymph node-negative, stage I/IIA breast cancer patients randomized to RT after breast-conserving surgery. Outcomes were analyzed at 10 years for ipsilateral breast tumor recurrence (IBTR) and any recurrence and 15 years for breast cancer specific death (BCSD).

Results: PDGFRb expression correlated with estrogen receptor negativity and younger age. An increased risk for any recurrence was noted in univariable analysis for the medium (HR 1.58, CI 95% 1.11-2.23, p = 0.011) or PDGFRb high group (1.49, 1.06-2.10, p = 0.021) compared to the low group. No differences in IBTR or BCSD risk were detected. RT benefit regarding IBTR risk was significant in the PDGFRb low (0.29, 0.12-0.67, p = 0.004) and medium (0.31, 0.16-0.59, p < 0.001) groups but not the PDGFRb high group (0.64, 0.36-1.11, p = 0.110) in multivariable analysis. Likewise, risk reduction for any recurrence was less pronounced in the PDGFRb high group. No significant interaction between RT and PDGFRb-score could be detected.

Conclusion: A higher PDGFRb-score conferred an increased risk of any recurrence, which partly can be explained by its association with estrogen receptor negativity and young age. Reduced RT benefit was noted among patients with high PDGFRb, however without significant interaction.
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http://dx.doi.org/10.1007/s10549-021-06136-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062362PMC
May 2021

Implementation of National Guidelines increased survival in advanced ovarian cancer - A population-based nationwide SweGCG study.

Gynecol Oncol 2021 Apr 10;161(1):244-250. Epub 2021 Feb 10.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

Aim: The first Swedish National Guidelines for Ovarian Cancer (NGOC) were published in 2012. We aimed to evaluate surgical outcomes and survival in patients with stage IIIC-IV disease, before and after the NGOC implementation.

Method: Women with primary epithelial ovarian cancer, FIGO stage IIIC-IV, registered in the Swedish Quality Registry for Gynecologic Cancer 2008-2011 and 2013-2016 were included. Surgical outcomes were analyzed, including frequency of complete cytoreduction (R0). Relative survival (RS) and excess mortality rate ratios (EMRRs) were computed as measures of survival. Univariable and multivariable regression (Poisson) were calculated.

Results: In total, 3728 women were identified, 1746 before and 1982 after NGOC. After adjusting for age and stage, survival was improved 2013-2016 vs. 2008-2011 (EMRR 0.89; 95%CI:0.82-0.96, p < 0.05). For women undergoing primary debulking surgery (PDS), R0 frequency (28.9% vs. 53.3%; p < 0.001) and 5-year RS (29.6% (95%CI:26.8-32.8) vs. 37.4% (95%CI:33.6-41.7)) were increased, but fewer patients (58% vs. 44%, p < 0.001) underwent PDS after NGOC implementation. Median survival for the PDS cohort increased from 35 months (95%CI,32.8-39.2) to 43 months (95%CI,40.9-46.4). In the neoadjuvant chemotherapy (NACT) + interval debulking surgery (IDS) cohort, R0 increased (36.8% to 50.1%, p < 0.001), but not 5-year RS (17.5% vs. 20.7%, ns). Compared to PDS, the EMRR was 1.32 (95%CI,1.19-1.47, p < 0.001) for NACT+IDS and 3.00 (95%CI,2.66-3.38, p < 0.001) for chemotherapy alone. In multivariable analyses, PDS, R0, age ≤ 70 years, and stage IIIC were found to be independent factors for improved RS.

Conclusion: Implementation of the first National Guidelines for Ovarian Cancer improved relative survival in advanced ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.012DOI Listing
April 2021

Patient-reported pain after surgical removal of leukoplakia - an observational 1-year follow-up study.

Acta Odontol Scand 2021 Jan 21:1-6. Epub 2021 Jan 21.

Department of Oral Medicine and Pathology, Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objective: Oral leukoplakia (OL) presents as a white lesion of the oral mucosa and is not typically associated with the sensation of pain. OL should be surgically removed when possible because it is considered a potentially malignant oral disorder (PMOD). This study assessed the pain sensations experienced by patients in association with the occurrence and surgical treatment of OL.

Methods: Inclusion criteria were: a clinical diagnosis of OL; biopsy excision; and observation for at least 12 months in the ORA-LEU-CAN study. At the first visit, all the patients were asked about the occurrence of symptoms within the lesion. Ninety-four subjects were assessed over a period of 1 year. All patients underwent complete removal of OL. The patient cohort was divided into three sub-groups: (i) no pain before excision and at the 1-year follow-up; (ii) pain before excision; and (iii) pain at the 1-year follow-up.

Results: Overall, pain was reported by 21.3% of the patients at the study start whereas 13.8% of the patients reported pain 1 year after surgical treatment. Patient-reported pain from the lesion at study inclusion was significantly associated with lesions found on the lateral side of the tongue (=.002). Pain reported by patients one year after surgery was significantly related to female gender (=.038) and the presence of epithelial cell dysplasia (=.022).

Conclusion: We conclude that surgical removal of OL results in a low risk of long-term post-surgical pain. However, OL located on the lateral side of the tongue and in OL with dysplasia are more likely to be associated with pain.
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http://dx.doi.org/10.1080/00016357.2020.1869826DOI Listing
January 2021

Immune Infiltrate in the Primary Tumor Predicts Effect of Adjuvant Radiotherapy in Breast Cancer; Results from the Randomized SweBCG91RT Trial.

Clin Cancer Res 2021 Feb 4;27(3):749-758. Epub 2020 Nov 4.

Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

Purpose: Tumor-infiltrating immune cells play a key role in tumor progression. The purpose of this study was to analyze whether the immune infiltrate predicts benefit from postoperative radiotherapy in a large randomized breast cancer radiotherapy trial.

Experimental Design: In the SweBCG91RT trial, patients with stage I and II breast cancer were randomized to breast-conserving surgery (BCS) and postoperative radiotherapy or to BCS only and followed for a median time of 15.2 years. The primary tumor immune infiltrate was quantified through two independent methods: IHC and gene expression profiling. For IHC analyses, the absolute stromal area occupied by CD8 T cells and FOXP3 T cells, respectively, was used to define the immune infiltrate. For gene expression analyses, immune cells found to be prognostic in independent datasets were pooled into two groups consisting of antitumoral and protumoral immune cells, respectively.

Results: An antitumoral immune response in the primary tumor was associated with a reduced risk of breast cancer recurrence and predicted less benefit from adjuvant radiotherapy. The interaction between radiotherapy and immune phenotype was significant for any recurrence in both the IHC and gene expression analyses ( = 0.039 and = 0.035) and was also significant for ipsilateral breast tumor recurrence in the gene expression analyses ( = 0.025).

Conclusions: Patients with an antitumoral immune infiltrate in the primary tumor have a reduced risk of any recurrence and may derive less benefit from adjuvant radiotherapy. These results may impact decisions regarding postoperative radiotherapy in early breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3299DOI Listing
February 2021

Estimates of lung and pancreatic cancer survival in Sweden with and without inclusion of death certificate initiated (DCI) cases.

Acta Oncol 2020 Nov 16;59(11):1322-1328. Epub 2020 Oct 16.

National Board of Health and Welfare, Stockholm, Sweden.

Introduction: International differences in cancer incidence and survival may partly reflect differences in cancer registration practices. As opposed to most other National Cancer Registries, Death Certificate Initiated (DCI) cases are not included in the Swedish Cancer Register. We characterized cases not reported to the Swedish Cancer Register and assessed the impact of inclusion of DCI cases on the completeness and estimates of one-year lung and pancreatic cancer survival.

Methods: We used information in the Swedish Cause of Death Register to identify individuals in two Health Care Regions (West and Uppsala Örebro) with lung or pancreatic cancer as cause of death in 2013. These records were cross-linked to the Cancer Register to identify individuals without a corresponding cancer registration, i.e. Death Certificate Notified (DCN) cases. DCN cases were cross-linked to the Patient Register to retrieve hospital discharge information to confirm the diagnosis. In a separate step, trace-back of DCN cases was performed to access medical records to validate the diagnosis.

Results: Following validity checks, an estimated 16% and 34% of individuals with a diagnosis of lung or pancreatic cancer, respectively, had not been reported to the SCR. Non-reported patients were older and had a considerable poorer survival than those included in the SCR. Inclusion of DCI cases decreased one-year lung cancer overall survival from 45% to 41%. The corresponding decrease for pancreatic cancer was five percentage points, from 29% to 24%.

Conclusions: Lung and pancreatic cancers are underreported to the SCR yielding too low incidence rates and upward biased survival estimates. We conclude that implementation of systematic death certificate processing with trace-back is feasible also within the Swedish system with regionalized cancer reporting. Verifying registrability by use of information in the Patient Register provided a good approximation of "corrected" survival estimates based on chart review.
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http://dx.doi.org/10.1080/0284186X.2020.1826572DOI Listing
November 2020

Primary treatment and relative survival by stage and age in vulvar squamous cell carcinoma: A population-based SweGCG study.

Gynecol Oncol 2020 12 26;159(3):663-671. Epub 2020 Sep 26.

Department of Oncology, and Department of Biomedical and Clinical Sciences, Linköping University, SE-58185 Linköping, Sweden.

Objective: Vulvar cancer affects mainly elderly women and with an ageing population the incidence has increased. We explored the primary treatment patterns and relative survival of patients with vulvar squamous cell carcinoma (VSCC) by stage and age-group.

Methods: A population-based nationwide study on women diagnosed with VSCC between 2012 and 2016 and registered in the Swedish Quality Registry for Gynecologic Cancer (SQRGC). Main outcome was 5-year relative survival (RS) estimated by the Pohar Perme method. The relative risk of excess mortality (EMRR) between different groups was analyzed by Poisson regression. The age-standardized relative survival (AS-RS) was estimated for the total cohort.

Results: Median follow-up time was 41 months. The study population included 657 women; 33% were ≥ 80 years old. FIGO stage I was most common (55%). Primary surgery was performed in 96% stage I, 65% stage II, 80% stage III and 28% stage IV. In women ≥80 years, exploration of the groins and chemoradiotherapy was less often performed. They also received lower mean doses of radiation than younger women. The 5-year AS-RS was 74%. 5-year RS was 84% for stage I, 60% for stage II, 54% for stage III and 35% for stage IV. The EMRR for women ≥80 years compared with women <60 years was 4.3 (p < 0.001); 4.9 (p < 0.001) for stages I-II and 3.5(p = 0.007) for stage III.

Conclusions: In general, primary treatment of patients with vulvar squamous cell carcinoma in Sweden adhered to guidelines. Areas of improvement include treatment for stage II and for the very old.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.027DOI Listing
December 2020

Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast-conserving surgery: a long-term follow-up of the SweBCG91-RT randomised trial.

Mol Oncol 2020 11 28;14(11):2713-2726. Epub 2020 Sep 28.

Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.

Experimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) after adjuvant radiotherapy (RT) in primary breast cancer. HGF, phosphorylated Met (pMet) and phosphorylated Akt (pAkt) were evaluated immunohistochemically on tissue microarrays from 1004 patients in the SweBCG91-RT trial, which randomly assigned patients to breast-conserving therapy, with or without adjuvant RT. HGF was evaluated in the stroma (HGF ); pMet in the membrane (pMet ); HGF, pMet and pAkt in the cytoplasm (HGF , pMet , pAkt ); and pAkt in the nucleus (pAkt ). The prognostic and treatment predictive effects were evaluated to primary endpoint IBTR as first event during the first 5 years. Patients with tumours expressing low levels of HGF and pMet and high levels of pAkt derived a larger benefit from RT [hazard ratio (HR): 0.11 (0.037-0.30), 0.066 (0.016-0.28) and 0.094 (0.028-0.31), respectively] compared to patients with high expression of HGF and pMet , and low pAkt [HR: 0.36 (0.19-0.67), 0.35 (0.20-0.64) and 0.47 (0.32-0.71), respectively; interaction analyses: P = 0.052, 0.035 and 0.013, respectively]. These differences remained in multivariable analysis when adjusting for patient age, tumour size, histological grade, St Gallen subtype and systemic treatment (interaction analysis, P-values: 0.085, 0.027, and 0.023, respectively). This study suggests that patients with immunohistochemically low HGF , low pMet and high pAkt may derive an increased benefit from RT after breast-conserving surgery concerning the risk of developing IBTR.
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http://dx.doi.org/10.1002/1878-0261.12803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607179PMC
November 2020

Impact of patient, primary tumor and metastatic pattern including tumor location on survival in patients undergoing ablation or resection for colorectal liver metastases: A population-based national cohort study.

Eur J Surg Oncol 2021 02 6;47(2):375-383. Epub 2020 Aug 6.

Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden; Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.

Introduction: Selecting the optimal treatment strategy for patients with colorectal liver metastases (CRLM) aim to improve survival for the total cohort. Following the introduction of laparoscopic resections and ablation, localization may direct choice of method. The aim with this study was to re-evaluate prognostic factors that should be considered at the preoperative multidisciplinary tumor board, based on a national population cohort.

Materials And Methods: A national cohort with radically operated colorectal cancer in 2009-2013, also treated for CRLM was identified in Swedish national registries. Prognostic factors were identified and evaluated in multivariable analyses.

Results: 1200 patients treated with resection and 125 with ablation only were included in the study cohort. Relative five-year survival was 54.7% (50.9%-58.4%) and 32.0% (22.4%-41.9%), respectively). High age, acute surgery and complications at time of primary tumor resection remained important risk factors at liver surgery, as well as the primary tumor characteristics; vascular invasion and high lymph node ratio. As for metastatic pattern; tumor size, location in segment 4, 6, 7 or 8, multiple metastatic sites and progress after preoperative chemotherapy were significant risk factors. In multivariate analyses, ablation therapy doubled the risk of death within 5 years. This strong negative impact was confirmed in a weighted propensity score analysis (HR = 2.1 (95 % CI 1.5 -3.0)).

Conclusion: Segmental localization and tumor size were prognostic factors but also patient and primary tumor factors significantly impacted survival after intervention for CRLM. Long-term survival was significantly lower after ablation therapy compared to surgical resection.
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http://dx.doi.org/10.1016/j.ejso.2020.07.030DOI Listing
February 2021

Evidence for Increased Susceptibility to Breast Cancer From Exposure to Ionizing Radiation Due to a Familial History of Breast Cancer: Results From the Swedish Hemangioma Cohort.

Am J Epidemiol 2021 01;190(1):76-84

Women with a history of breast cancer among family members are at increased risk for breast cancer. However, it is unknown whether a familial breast cancer history (FBCH) also increases individual susceptibility to breast cancer from radiation exposure. In this cohort study, 17,200 female Swedish hemangioma patients with 1,079 breast cancer cases diagnosed between 1958 and 2013, exposed to ionizing radiation in infancy, were linked to their first-degree relatives. The association between FBCH and radiation-induced breast cancer risk was assessed. Further, the relevance for breast cancer radiotherapy and mammography screening was evaluated. On average, the radiation-induced excess relative risk and excess absolute risk of breast cancer at age 50 years were 0.51 Gy-1 (95% confidence interval (CI): 0.33, 0.71) and 10.8 cases/10,000 person-years/Gy (95% CI: 7.0, 14.6), respectively. Radiation risk was higher by a factor of 2.7 (95% CI: 1.0, 4.8; P = 0.05) if 1 first-degree relative was affected by breast cancer. For whole-breast standard radiotherapy at age 40 years with a contralateral breast dose of 0.72 Gy, the 20-year radiation-related excess risk of contralateral breast cancer was estimated to increase from 0.6% for women without FBCH to 1.7% for women with FBCH. In a biennial mammography screening program at ages 40-74 years, radiation risk up to age 80 years would increase from 0.11% for women without FBCH to 0.29% for women with FBCH.
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http://dx.doi.org/10.1093/aje/kwaa163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784527PMC
January 2021

Disease mapping of early- and late-stage cancer to monitor inequalities in early detection: a study of cutaneous malignant melanoma.

Eur J Epidemiol 2020 Jun 30;35(6):537-547. Epub 2020 Apr 30.

UK Small Area Health Statistics Unit (SAHSU), Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.

We consider disease mapping of early- and late-stage cancer, in order to identify and monitor inequalities in early detection. Our method is demonstrated by mapping cancer incidence at high geographical resolution using data on 10,302 cutaneous malignant melanoma (CMM) cases within the 3.7 million population of South-West Sweden. The cases were geocoded into small-areas, each with a population size between 600 and 2600 and accessible socio-demographic data. Using the disease mapping application Rapid Inquiry Facility (RIF) 4.0, we produced regional maps to visualise spatial variations in stage I, II and III-IV CMM incidences, complemented by local maps to explore the variations within two urban areas. Pronounced spatial disparities in stage I CMM incidence were revealed by the regional and local maps. Stage I CMM incidence was markedly higher in wealthier small-areas, in particular within each urban area. A twofold higher stage I incidence was observed, on average, in the wealthiest small-areas (upper quintile) than in the poorest small-areas (lower quintile). We identified in the regional map of stage III-IV CMM two clusters of higher or lower than expected late-stage incidences which were quite distinct from those identified for stage I. In conclusion, our analysis of CMM incidences supported the use of this method of cancer stage incidence mapping for revealing geographical and socio-demographic disparities in cancer detection.
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http://dx.doi.org/10.1007/s10654-020-00637-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320924PMC
June 2020

No Increased Cardiac Mortality or Morbidity of Radiation Therapy in Breast Cancer Patients After Breast-Conserving Surgery: 20-Year Follow-up of the Randomized SweBCGRT Trial.

Int J Radiat Oncol Biol Phys 2020 07 14;107(4):701-709. Epub 2020 Apr 14.

Department of Clinical Sciences, Faculty of Medicine, Lund, Lund University, Sweden; Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.

Purpose: Radiation therapy (RT) after breast-conserving surgery reduces locoregional recurrences and improves survival but may cause late side effects. The main purpose of this paper was to investigate long-term side effects after whole breast RT in a randomized clinical trial initiated in 1991 and to report dose-volume data based on individual 3-dimensional treatment plans for organs at risk.

Methods And Materials: The trial included 1187 patients with T1-2 N0 breast cancer randomized to postoperative tangential whole breast RT or no further treatment. The prescription dose to the clinical target volume was 48 to 54 Gy. We present 20-year follow-up on survival, cause of death, morbidity, and later malignancies. For a cohort of patients (n = 157) with accessible computed tomography-based 3-dimensional treatment plans in Dicom-RT format, dose-volume descriptors for organs at risk were derived. In addition, these were compared with dose-volume data for a cohort of patients treated with contemporary RT techniques.

Results: The cumulative incidence of cardiac mortality was 12.4% in the control group and 13.0% in the RT group (P = .8). There was an increase in stroke mortality: 3.4% in the control group versus 6.7% in the RT group (P = .018). Incidences of contralateral breast cancer and lung cancer were similar between groups. The median D (range) heart dose for left-sided treatments was 3.0 Gy (1.1-8.1), and the corresponding value for patients treated in 2017 was 1.5 Gy (0.4-6.0).

Conclusions: In this trial, serious late side effects of whole breast RT were limited and less than previously reported in large meta-analyses. We observed no increase in cardiac mortality in irradiated patients. Doses to the heart were a median D of 3.0 Gy for left-sided RT. The observed increase in stroke mortality may partly be secondary to cardiac side effects, complications to anticoagulant treatment, or to chance, rather than a direct side effect of tangential whole breast irradiation.
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http://dx.doi.org/10.1016/j.ijrobp.2020.04.003DOI Listing
July 2020

Randomized trial of a left ventricular assist device as destination therapy versus guideline-directed medical therapy in patients with advanced heart failure. Rationale and design of the SWEdish evaluation of left Ventricular Assist Device (SweVAD) trial.

Eur J Heart Fail 2020 04 26;22(4):739-750. Epub 2020 Feb 26.

Departments of Cardiothorax Surgery and Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden.

Aims: Patients with advanced heart failure (AdHF) who are ineligible for heart transplantation (HTx) can become candidates for treatment with a left ventricular assist device (LVAD) in some countries, but not others. This reflects the lack of a systematic analysis of the usefulness of LVAD systems in this context, and of their benefits, limitations and cost-effectiveness. The SWEdish evaluation of left Ventricular Assist Device (SweVAD) study is a Phase IV, prospective, 1:1 randomized, non-blinded, multicentre trial that will examine the impact of assignment to mechanical circulatory support with guideline-directed LVAD destination therapy (GD-LVAD-DT) using the HeartMate 3 (HM3) continuous flow pump vs. guideline-directed medical therapy (GDMT) on survival in a population of AdHF patients ineligible for HTx.

Methods: A total of 80 patients will be recruited to SweVAD at the seven university hospitals in Sweden. The study population will comprise patients with AdHF (New York Heart Association class IIIB-IV, INTERMACS profile 2-6) who display signs of poor prognosis despite GDMT and who are not considered eligible for HTx. Participants will be followed for 2 years or until death occurs. Other endpoints will be determined by blinded adjudication. Patients who remain on study-assigned interventions beyond 2 years will be asked to continue follow-up for outcomes and adverse events for up to 5 years.

Conclusion: The SweVAD study will compare survival, medium-term benefits, costs and potential hazards between GD-LVAD-DT and GDMT and will provide a valuable reference point to guide destination therapy strategies for patients with AdHF ineligible for HTx.
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http://dx.doi.org/10.1002/ejhf.1773DOI Listing
April 2020

Return to work after oropharyngeal cancer treatment-Highlighting a growing working-age population.

Head Neck 2020 08 24;42(8):1893-1901. Epub 2020 Feb 24.

Department of Surgical Sciences, Section of Otorhinolaryngology and Head & Neck Surgery, Uppsala University, Uppsala, Sweden.

Background: To describe the frequency of patients returning to work after treatment for oropharyngeal cancer and to identify predictors and physical barriers that might interfere with the return to work process.

Methods: Cross-sectional study including 295 patients. Data were collected regarding work/sick leave situation at 1 month before diagnosis and 15 months after diagnosis. The situation before diagnosis was retrospectively recalled by the patients. Two subscales and two single items from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35 were used. Data were analyzed with multivariate logistic regression.

Results: Fifteen months after diagnosis, 212 patients (72%) were working. To be working 15 months after diagnosis was associated with working before diagnosis. Swallowing difficulties, problems talking on the telephone, and physical appearance were negatively associated with returning to work.

Conclusions: The large number of individuals returning to work is encouraging for patients diagnosed with oropharyngeal cancer.
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http://dx.doi.org/10.1002/hed.26123DOI Listing
August 2020

Health-related quality of life among tonsillar carcinoma patients in Sweden in relation to treatment and comparison with quality of life among the population.

Head Neck 2020 05 10;42(5):860-872. Epub 2020 Feb 10.

Department of Otorhinolaryngology-Head and Neck Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: The health-related quality of life (HRQOL) of tonsillar carcinoma survivors was explored to investigate any HRQOL differences associated with tumor stage and treatment. The survivors' HRQOL was also compared to reference scores from the population.

Methods: In this exploratory cross-sectional study patients were invited 15 months after their diagnosis and asked to answer two quality of life questionnaires (EORTC QLQ- C30, EORTC QLQ- HN35), 405 participated.

Results: HRQOL was associated with gender, with males scoring better than females on a few scales. Patients' HRQOL was more associated with treatment than tumor stage. Patients' HRQOL was worse than that in an age- and sex-matched reference group from the normal population, the largest differences were found for problems with dry mouth followed by problems with sticky saliva, senses, swallowing and appetite loss.

Conclusions: The tonsillar carcinoma patients had a worse HRQOL compared to the general population one year after treatment.
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http://dx.doi.org/10.1002/hed.26064DOI Listing
May 2020

Association of Baseline Prostate-Specific Antigen Level With Long-term Diagnosis of Clinically Significant Prostate Cancer Among Patients Aged 55 to 60 Years: A Secondary Analysis of a Cohort in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

JAMA Netw Open 2020 01 3;3(1):e1919284. Epub 2020 Jan 3.

Department of Surgery, Division of Urology, Rush Medical College, Chicago, Illinois.

Importance: The use of prostate-specific antigen (PSA) screening for prostate cancer is controversial because of the risk of overdiagnosis and overtreatment of indolent cancers. Optimal screening strategies are highly sought.

Objective: To estimate the long-term risk of any prostate cancer and clinically significant prostate cancer based on baseline PSA levels among men aged 55 to 60 years.

Design, Setting, And Participants: This secondary analysis of a cohort in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial uses actuarial analysis to analyze the association of baseline PSA levels with long-term risk of any prostate cancer and of clinically significant prostate cancer among men aged 55 to 60 years enrolled in the screening group of the trial between 1993 and 2001.

Exposure: Single PSA measurement at study entry.

Main Outcomes And Measures: Long-term risk of any prostate cancer and clinically significant prostate cancer diagnoses.

Results: There were 10 968 men aged 55 to 60 years (median [interquartile range] age, 57 [55-58] years) at study enrollment in the screening group of the PLCO Cancer Screening Trial who had long-term follow-up. Actuarial 13-year incidences of clinically significant prostate cancer diagnosis among participants with a baseline PSA of 0.49 ng/mL or less was 0.4% (95% CI, 0%-0.8%); 0.50-0.99 ng/mL, 1.5% (95% CI, 1.1%-1.9%); 1.00-1.99 ng/mL, 5.4% (95% CI, 4.4%-6.4%); 2.00-2.99 ng/mL, 10.6% (95% CI, 8.3%-12.9%); 3.00-3.99 ng/mL, 15.3% (95% CI, 11.4%-19.2%); and 4.00 ng/mL and greater, 29.5% (95% CI, 24.2%-34.8%) (all pairwise log-rank P ≤ .004). Only 15 prostate cancer-specific deaths occurred during 13 years of follow-up, and 9 (60.0%) were among men with a baseline PSA level of 2.00 ng/mL or higher.

Conclusions And Relevance: In this secondary analysis of a cohort from the PLCO Cancer Screening Trial, baseline PSA levels among men aged 55 to 60 years were associated with long-term risk of clinically significant prostate cancer. These findings suggest that repeated screening can be less frequent among men aged 55 to 60 years with a low baseline PSA level (ie, <2.00 ng/mL) and possibly discontinued among those with baseline PSA levels of less than 1.00 ng/mL.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.19284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991265PMC
January 2020

Increased Overall Mortality Even after Risk Reducing Surgery for -Positive Women in Western Sweden.

Genes (Basel) 2019 12 16;10(12). Epub 2019 Dec 16.

Department of Oncology, Institution of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, 413 45 Gothenburg, Sweden.

Women with variants have a high lifetime risk of developing breast and ovarian cancer. The aim of this study was to investigate the standard incidence ratios (SIR) for breast and ovarian cancer and standard mortality ratios (SMR) in a population-based cohort of women in Western Sweden, under surveillance and after risk reducing surgery. Women who tested positive for a variant between 1995-2016 ( = 489) were prospectively registered and followed up for cancer incidence, risk reducing surgery and mortality. The Swedish Cancer Register was used to compare breast and ovarian cancer incidence and mortality with and without risk reducing surgery for women with variants in comparison to women in the general population. SIR for breast cancer under surveillance until risk-reducing mastectomy (RRM) was 14.0 (95% CI 9.42-20.7) and decreased to 1.93 (95% CI 0.48-7.7) after RRM. The SIR for ovarian cancer was 124.6 (95% CI 59.4-261.3) under surveillance until risk reducing salpingo-oophorectomy (RRSO) and decreased to 13.5 (95% CI 4.34-41.8) after RRSO. The SMR under surveillance before any risk reducing surgery was 5.56 (95% 2.09-14.8) and after both RRM and RRSO 4.32 (95% CI 1.62-11.5). Women with cancer diagnoses from the pathology report after risk reducing surgery were excluded from the analyses. Risk reducing surgery reduced the incidence of breast and ovarian cancer in women with variants. However, overall mortality was significantly increased in comparison to the women in the general population and remained elevated even after risk reducing surgery. These findings warrant further research regarding additional measures for these women.
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http://dx.doi.org/10.3390/genes10121046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947302PMC
December 2019

Recurrence rates after surgical removal of oral leukoplakia-A prospective longitudinal multi-centre study.

PLoS One 2019 6;14(12):e0225682. Epub 2019 Dec 6.

Department of Oral Medicine and Pathology, Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Oral leukoplakia (OL) is a potentially malignant oral disorder. The Gold Standard treatment is to remove surgically the OL. Despite optimal surgery, the recurrence rates are estimated to be 30%. The reason for this is unknown. The aim of this study was to investigate the clinical factors that correlate with recurrence after surgical removal of OL. In a prospective study data were collected from 226 patients with OL. Forty-six patients were excluded due to incomplete records or concomitant presence of other oral mucosal diseases. Overall, 180 patients proceeded to analysis (94 women and 86 men; mean age, 62 years; age range, 28-92 years). Clinical data, such as gender, diagnosis (homogeneous/non-homogeneous leukoplakia), location, size, tobacco and alcohol use, verified histopathological diagnosis, and clinical photograph, were obtained. In patients who were eligible for surgery, the OL was surgically removed with a margin. To establish recurrence, a healthy mucosa between the surgery and recurrence had to be confirmed in the records or clinical photographs. Statistical analysis was performed with the level of significance set at P<0.05. Of the 180 patients diagnosed with OL, 57% (N = 103) underwent surgical removal in toto. Recurrence was observed in 43 OL. The cumulative incidence of recurrence of OL was 45% after 4 years and 49% after 5 years. Fifty-six percent (N = 23) of the non-homogeneous type recurred. Among snuff-users 73% (N = 8) cases of OL recurred. A non-homogeneous type of OL and the use of snuff were significantly associated with recurrence after surgical excision (P = 0.021 and P = 0.003, respectively). Recurrence was also significantly associated with cancer transformation (P<0.001). No significant differences were found between recurrence and any of the following: dysplasia, site of lesion, size, multiple vs. solitary OL, gender, age, use of alcohol or smoking. In conclusion, clinical factors that predict recurrence of OL are non-homogeneous type and use of snuff.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225682PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897554PMC
April 2020

Risk of vaginal cancer among hysterectomised women with cervical intraepithelial neoplasia: a population-based national cohort study.

BJOG 2020 03 14;127(4):448-454. Epub 2019 Dec 14.

Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objective: To study the risk of vaginal cancer among hysterectomised women with and without cervical intraepithelial neoplasia (CIN).

Design: Population-based national cohort study.

Setting And Population: All Swedish women, 5 million in total, aged 20 and up, 1987-2011 using national registries.

Methods: The study cohort was subdivided into four exposure groups: hysterectomised with no previous history of CIN3 and without prevalent CIN at hysterectomy; hysterectomised with a history of CIN3/adenocarcinoma in situ (AIS); hysterectomised with prevalent CIN at hysterectomy; non-hysterectomised.

Main Outcome Measure: Vaginal cancer.

Results: We identified 898 incident cases of vaginal cancer. Women with prevalent CIN at hysterectomy and those with a history of CIN3/AIS had incidence rates (IR) of vaginal cancer of 51.3 (95% CI 34.4-76.5) and 17.1 (95% CI 12.5-23.4) per 100 000, respectively. Age-adjusted IR-ratios (IRRs) compared with hysterectomised women with benign cervical history were 21.0 (95% CI 13.4-32.9) and 5.81 (95% CI 4.00-8.43), respectively. IR for non-hysterectomised women was 0.87 (95% CI 0.81-0.93) and IRR was 0.37 (95% CI 0.30-0.46). In hysterectomised women with prevalent CIN, the IR remained high after 15 years of follow up: 65.7 (95% CI 21.2-203.6).

Conclusions: Our findings suggest that hysterectomised women with prevalent CIN at surgery should be offered surveillance. Hysterectomised women without the studied risk factors have a more than doubled risk of contracting vaginal cancer compared with non-hysterectomised women in the general population. Still, the incidence rate does not justify screening.

Tweetable Abstract: High risk of contracting vaginal cancer among hysterectomised women having prevalent CIN at surgery.
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http://dx.doi.org/10.1111/1471-0528.16028DOI Listing
March 2020

Clinicogenomic Radiotherapy Classifier Predicting the Need for Intensified Locoregional Treatment After Breast-Conserving Surgery for Early-Stage Breast Cancer.

J Clin Oncol 2019 12 16;37(35):3340-3349. Epub 2019 Oct 16.

Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

Purpose: Most patients with early-stage breast cancer are treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) to prevent locoregional recurrence (LRR). However, no genomic tools are used currently to select the optimal RT strategy.

Methods: We profiled the transcriptome of primary tumors on a clinical grade assay from the SweBCG91-RT trial, in which patients with node-negative breast cancer were randomly assigned to either whole-breast RT after BCS or no RT. We derived a new classifier, Adjuvant Radiotherapy Intensification Classifier (ARTIC), comprising 27 genes and patient age, in three publicly available cohorts, then independently validated ARTIC for LRR in 748 patients in SweBCG91-RT. We also compared previously published genomic signatures for ability to predict benefit from RT in SweBCG91-RT.

Results: ARTIC was highly prognostic for LRR in patients treated with RT (hazard ratio [HR], 3.4; 95% CI, 2.0 to 5.9; < .001) and predictive of RT benefit ( = .005). Patients with low ARTIC scores had a large benefit from RT (HR, 0.33 [95% CI, 0.21 to 0.52], < .001; 10-year cumulative incidence of LRR, 6% 21%), whereas those with high ARTIC scores benefited less from RT (HR, 0.73 [95% CI, 0.44 to 1.2], = .23; 10-year cumulative incidence of LRR, 25% 32%). In contrast, none of the eight previously published signatures were predictive of benefit from RT in SweBCG91-RT.

Conclusion: ARTIC identified women with a substantial benefit from RT as well as women with a particularly elevated LRR risk in whom whole-breast RT was not sufficiently effective and, thus, in whom intensified treatment strategies such as tumor-bed boost, and possibly regional nodal RT, should be considered. To our knowledge, ARTIC is the first classifier validated as predictive of benefit from RT in a phase III clinical trial with patients randomly assigned to receive or not receive RT.
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http://dx.doi.org/10.1200/JCO.19.00761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901281PMC
December 2019

Early mortality after diagnosis of cancer of the head and neck - A population-based nationwide study.

PLoS One 2019 2;14(10):e0223154. Epub 2019 Oct 2.

Division of Speech language pathology, Audiology and Otorhinolaryngology, Department of Clinical and Experimental medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.

Background: Cancers of the head and neck have a high mortality rate, and roughly 10% of the patients die within six months of diagnosis. To our knowledge little has been written about this group. We wished to identify risk factors for early death, to predict and monitor patients at risk better and, if possible, avoid unjustified major treatment.

Methods And Findings: This population-based nationwide study from the Swedish Head and Neck Cancer Register (SweHNCR) included data from 2008-2015 and 9733 patients at potential risk of early death. A total of 925 (9.5%) patients died within six months. For every year older the patients became, the risk of early death increased by 2.3% (p<0.001). The relative risk of death was 3.37 times higher (237%) for patients with WHO score 1 compared with WHO score 0. A primary tumour in the hypopharynx correlated with a 24% increased risk over the oral cavity (p<0.024). Patients with stage IV disease had a 3.7 times greater risk of early death than those with stage I (p<0.001). As expected, a 12 times increased risk of early death was noted in the palliative treatment group, compared to the curative group. Limitations to this study were that the actual cause of death was not recorded in the SweHNCR, and that socioeconomic factors, alcohol consumption, smoking habits, and HPV status, were not reported in SweHNCR until 2015. However, the fact that this is a population-based nationwide study including 9733 patients compensates for some of these limitations.

Conclusions: Identification of patients at increased risk of early death shows that older patients with advanced disease, increased WHO score, primary tumour in the hypopharynx, and those given palliative treatment, are more likely than the others to die from head and neck cancer within six months of diagnosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223154PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774523PMC
March 2020

Comprehensive Transcriptomic Profiling Identifies Breast Cancer Patients Who May Be Spared Adjuvant Systemic Therapy.

Clin Cancer Res 2020 01 26;26(1):171-182. Epub 2019 Sep 26.

Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.

Purpose: There is currently no molecular signature in clinical use for adjuvant endocrine therapy omission in breast cancer. Given the unique trial design of SweBCG91-RT, where adjuvant endocrine and chemotherapy were largely unadministered, we sought to evaluate the potential of transcriptomic profiling for identifying patients who may be spared adjuvant endocrine therapy.

Experimental Design: We performed a whole-transcriptome analysis of SweBCG91-RT, a randomized phase III trial of ± radiotherapy after breast-conserving surgery for node-negative stage I-IIA breast cancer. Ninety-two percent of patients were untreated by both adjuvant endocrine therapy and chemotherapy. We calculated 15 transcriptomic signatures from the literature and combined them into an average genomic risk, which was further used to derive a novel 141-gene signature (MET141). All signatures were then independently examined in SweBCG91-RT and in the publicly available METABRIC cohort.

Results: In SweBCG91-RT, 454 patients were node-negative, postmenopausal, and systemically untreated with ER-positive, HER2-negative cancers, which constitutes a low-risk subgroup and potential candidates for therapy omission. Most transcriptomic signatures were highly prognostic for distant metastasis, but considerable discordance was observed on the individual patient level. Within the MET141 low-risk subgroup (lowest 25th percentile of scores), 95% of patients were free of metastasis at 15 years, even in the absence of adjuvant endocrine therapy. In a clinically low-risk subgroup of the METABRIC cohort not treated with systemic therapy, no breast cancer death occurred among the MET141 low-risk patients.

Conclusions: Transcriptomic profiling identifies patients with an excellent outcome without any systemic adjuvant therapy in clinically low-risk patients of the SweBCG91-RT and METABRIC cohorts.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1038DOI Listing
January 2020

Primary treatment patterns and survival of cervical cancer in Sweden: A population-based Swedish Gynecologic Cancer Group Study.

Gynecol Oncol 2019 11 30;155(2):229-236. Epub 2019 Aug 30.

Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, SE-58185 Linköping, Sweden.

Objective: Survival in cervical cancer has improved little over the last decades. We aimed to elucidate primary treatment patterns and survival.

Methods: Population-based study of patients included in the Swedish Quality Registry for Gynecologic Cancer diagnosed 2011-2015. Main outcome was 5-year relative survival (RS). Age-standardised RS (AS-RS) was estimated for the total cohort and for the pooled study population of squamous, adenosquamous-, adenocarcinoma.

Results: Median follow-up time was 4.6 years. The study population consisted of 2141 patients; 97% of the 2212 patients in the total cohort and the 5-year AS-RS was 71% and 70%, respectively. RS stage IB1: surgery alone 95% vs. 72% for definitive chemoradiotherapy (CT-RT) (p < 0.001). In stage IIA1 74% had CT-RT, and 47% of operated patients received adjuvant (CT)-RT. RS stage IB2: surgically treated 81% (69% received adjuvant (CT)-RT) vs. 76% for (CT)-RT (p = 0.73). RS stage IIB: 77% for CT-RT + brachytherapy (BT), 37% for RT + BT (p = 0.045) and 27% for RT-BT (p < 0.001). Stages III-IVA; <40% received CT-RT + BT, RS 45% vs. 18% for RT-BT (RR 4.1, p < 0.001). RS stage IVB 7%.

Conclusion: Primary treatment of cervical cancer in Sweden adhered to evidence-based standard of care. Areas of improvement include optimising treatment for stages III-IVA, and avoiding combining surgery and radiotherapy.
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http://dx.doi.org/10.1016/j.ygyno.2019.08.022DOI Listing
November 2019

Lymphovascular space invasion as a predictive factor for lymph node metastases and survival in endometrioid endometrial cancer - a Swedish Gynecologic Cancer Group (SweGCG) study.

Acta Oncol 2019 Nov 2;58(11):1628-1633. Epub 2019 Aug 2.

Department of Cancer Epidemiology, Lund University, Lund, Sweden.

The aim of this study is to evaluate the impact of lymphovascular space invasion (LVSI) on the risk of lymph node metastases and survival in endometrioid endometrial adenocarcinoma. As regard the study design, this is a cohort study based on prospectively recorded data. Patients with endometrioid endometrial adenocarcinoma registered in the Swedish Quality Registry for Gynecologic Cancer 2010-2017 with FIGO stages I-III and verified nodal status were identified ( = 1587). LVSI together with established risk factors, namely DNA ploidy, FIGO grade, myometrial invasion and age, were included in multivariable regression analyses with lymph node metastases as the dependent variable. Associations between the risk factors and overall and relative survival were included in multivariable models. Estimates of risk ratios (RR), hazard ratios (HR), excess mortality rate ratios (EMR), and 95% confidence intervals (95% CI) were calculated. The presence of LVSI presented the strongest association with lymph node metastases ( = 5.46, CI 3.69-8.07,  < .001) followed by deep myometrial invasion ( = 1.64, CI 1.13-2.37). In the multivariable survival analyses, LVSI (EMR = 7.69, CI 2.03-29.10,) and non-diploidy (EMR = 3.23, CI 1.25-8.41) were associated with decreased relative survival. In sub-analyses including only patients with complete para-aortic and pelvic lymphadenectomy and negative lymph nodes ( = 404), only LVSI ( = 2.50, CI 1.05-5.98) was associated with a worsened overall survival. This large nationwide study identified LVSI as the strongest independent risk factor for lymph node metastases and decreased survival in patients with endometrioid adenocarcinomas. Moreover, decreased overall survival was also seen in patients with LVSI-positive tumors and negative lymph nodes, indicating that hematogenous dissemination might also be important.
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http://dx.doi.org/10.1080/0284186X.2019.1643036DOI Listing
November 2019

Is leisure time sitting associated with mortality rates among men diagnosed with localized prostate cancer?

Eur J Cancer Prev 2020 03;29(2):134-140

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Objective: Being physically active postdiagnosis has been associated with lower rates of prostate cancer progression and mortality, but studies investigating postdiagnostic time spent sitting are lacking. We aim to study the association between leisure time sitting after a prostate cancer diagnosis and overall and prostate cancer-specific mortality.

Methods: Data from 4595 men in Sweden, diagnosed with localized prostate cancer between 1997-2002 and followed-up until the end of 2012, were analyzed. Time spent sitting during leisure time postdiagnosis was categorized into <2, 2-3, 3-4, and >4 h/day. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) of postdiagnosis leisure time sitting and a joint variable of sitting time and exercise, and time to overall or prostate cancer-specific death.

Results: The results showed no significant associations between postdiagnostic leisure time sitting and overall or prostate cancer-specific mortality rates. When the joint effect of both sitting and exercise time was considered, borderline significantly lower mortality rates for overall and prostate cancer-specific mortality were seen among participants that sat the least and exercised the most compared to the reference category with participants sitting the most and exercising least (HR: 0.75; 95% CI: 0.56-1.00 and HR: 0.61; 95% CI: 0.36-1.05, respectively).

Conclusions: No significant association between leisure time sitting and mortality rates among men diagnosed with localized prostate cancer was seen. This study does not support an association between leisure time sitting per se; however, being physically active may have beneficial effects on survival among men diagnosed with localized prostate cancer.
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http://dx.doi.org/10.1097/CEJ.0000000000000523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012357PMC
March 2020

Distribution of Locoregional Breast Cancer Recurrence in Relation to Postoperative Radiation Fields and Biological Subtypes.

Int J Radiat Oncol Biol Phys 2019 10 15;105(2):285-295. Epub 2019 Jun 15.

Division of Oncology and Pathology, Institute of Clinical Sciences, Lund University, Skane University Hospital, Lund, Sweden. Electronic address:

Purpose: To investigate incidence and location of locoregional recurrence (LRR) in patients who have received postoperative locoregional radiation therapy (LRRT) for primary breast cancer. LRR-position in relation to applied radiotherapy and the primary tumor biological subtype were analyzed with the aim of evaluating current target guidelines and radiation therapy techniques in relation to tumor biology.

Methods And Materials: Medical records were reviewed for all patients who received postoperative LRRT for primary breast cancer in southwestern Sweden from 2004 to 2008 (N = 923). Patients with LRR as a first event were identified (n = 57; distant failure and death were considered competing risks). Computed tomographic images identifying LRR were used to compare LRR locations with postoperative LRRT fields. LRR risk and distribution were then related to the primary breast cancer biologic subtype and to current target guidelines.

Results: Cumulative LRR incidence after 10 years was 7.1% (95% confidence interval [CI], 5.5-9.1). Fifty-seven of the 923 patients in the cohort developed LRR (30 local recurrences and 30 regional recurrences, of which 3 cases were simultaneous local and regional recurrence). Most cases of LRR developed fully (56%) or partially (26%) within postoperatively irradiated areas. The most common location for out-of-field regional recurrence was cranial to radiation therapy fields in the supraclavicular fossa. Patients with an estrogen receptor negative (ER-) (hazard ratio [HR], 4.6; P < .001; 95% CI, 2.5-8.4) or HER2+ (HR, 2.4; P = .007; 95% CI, 1.3-4.7) primary breast cancer presented higher risks of LRR compared with those with ER+ tumors. ER-/HER2+ tumors more frequently recurred in-field (68%) rather than marginally or out-of-field (32%). In addition, 75% of in-field recurrences derived from an ER- or HER+ tumor, compared with 45% of marginal or out-of-field recurrences. A complete pathologic response in the axilla after neoadjuvant treatment was associated with a lower degree of LRR risk (P = .022).

Conclusions: Incidence and location of LRR seem to be related to the primary breast cancer biologic subtype. Individualized LRRT according to tumor biology may be applied to improve outcomes.
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http://dx.doi.org/10.1016/j.ijrobp.2019.06.013DOI Listing
October 2019

Effect of Radiotherapy After Breast-Conserving Surgery Depending on the Presence of Tumor-Infiltrating Lymphocytes: A Long-Term Follow-Up of the SweBCG91RT Randomized Trial.

J Clin Oncol 2019 05 2;37(14):1179-1187. Epub 2019 Apr 2.

2 Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

Purpose: The effects of radiotherapy (RT) on the basis of the presence of stromal tumor infiltrating lymphocytes (TILs) have not been studied. The purpose of this study was to analyze the association of TILs with the effect of postoperative RT on ipsilateral breast tumor recurrence (IBTR) in a large randomized trial.

Methods: In the SweBCT91RT (Swedish Breast Cancer Group 91 Radiotherapy) trial, 1,178 patients with breast cancer stage I and II were randomly assigned to breast-conserving surgery plus postoperative RT or breast-conserving surgery only and followed for a median of 15.2 years. Tumor blocks were retrieved from 1,003 patients. Stromal TILs were assessed on whole-section hematoxylin-eosin-stained slides using a dichotomized cutoff of 10%. Subtypes were scored using immunohistochemistry on tissue microarray. In total, 936 patients were evaluated.

Results: Altogether, 670 (71%) of patients had TILs less than 10%. In a multivariable regression analysis with IBTR as dependent variable and RT, TILs, subtype, age, and grade as independent variables, RT (hazard ratio [HR], 0.42; 95% CI, 0.29 to 0.61; < .001), high TILs (HR, 0.61; 95% CI, 0.39 to 0.96, = .033) grade (3 1; HR, 2.17; 95% CI, 1.08 to 4.34; = .029), and age (≥ 50 < 50 years; HR, 0.55; 95% CI, 0.38 to 0.80; = .002) were predictive of IBTR. RT was significantly beneficial in the low TILs group (HR, 0.37; 95% CI, 0.24 to 0.58; < .001) but not in the high TILs group (HR, 0.58; 95% CI, 0.28 to 1.19; = .138). The test for interaction between RT and TILs was not statistically significant ( = .317).

Conclusion: This study shows that high values of TILs in the primary tumor independently seem to reduce the risk for an IBTR. Our findings further suggest that patients with breast cancer with low TILs may derive a larger benefit from RT regarding the risk of IBTR.
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http://dx.doi.org/10.1200/JCO.18.02157DOI Listing
May 2019

Radiation-induced genomic instability in breast carcinomas of the Swedish hemangioma cohort.

Genes Chromosomes Cancer 2019 09 12;58(9):627-635. Epub 2019 Apr 12.

Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Radiation-induced genomic instability (GI) is hypothesized to persist after exposure and ultimately promote carcinogenesis. Based on the absorbed dose to the breast, an increased risk of developing breast cancer was shown in the Swedish hemangioma cohort that was treated with radium-226 for skin hemangioma as infants. Here, we screened 31 primary breast carcinomas for genetic alterations using the OncoScan CNV Plus Assay to assess GI and chromothripsis-like patterns associated with the absorbed dose to the breast. Higher absorbed doses were associated with increased numbers of copy number alterations in the tumor genome and thus a more unstable genome. Hence, the observed dose-dependent GI in the tumor genome is a measurable manifestation of the long-term effects of irradiation. We developed a highly predictive Cox regression model for overall survival based on the interaction between absorbed dose and GI. The Swedish hemangioma cohort is a valuable cohort to investigate the biological relationship between absorbed dose and GI in irradiated humans. This work gives a biological basis for improved risk assessment to minimize carcinogenesis as a secondary disease after radiation therapy.
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http://dx.doi.org/10.1002/gcc.22757DOI Listing
September 2019