BackgroundSeveral cancer types have increased PFKFB3, a glycolytic enzyme for which potent inhibitors have been found. Inhibition of PFKFB3 impairs DNA repair after irradiation of cancer cells, making it a possible radiosensitization target. The SweBCG91RT trial, in which breast cancer patients were randomized to postoperative radiotherapy or not, was used to investigate PFKFB3 as a clinical marker of sensitivity to adjuvant radiotherapy.MethodsNuclear protein levels of PFKFB3 were assessed with immunohistochemistry in primary breast tumors (n = 970) and whole-cell RNA levels with microarray gene expression (n = 765). Multivariable competing risks regression analysis was employed for the effect of radiotherapy on incidence of ipsilateral breast tumor recurrence (IBTR), depending on PFKFB3 levels.ResultsTumors with high levels of nuclear protein and RNA had the largest effect on incidence of IBTR of adjuvant radiotherapy, however without evidence of an interaction. PFKFB3 RNA correlated with subtype, as high levels were more common among the human epidermal growth factor receptor 2 (HER2) positive and Luminal A subtypes than Luminal B and triple negative tumors.ConclusionHigh PFKFB3 is associated with a larger reduction of IBTR after radiotherapy but PFKFB3 cannot reliably be used as a predictive marker of sensitivity to adjuvant radiotherapy in breast cancer. PFKFB3 expression differed with subtype, indicating that it may be a better marker among Luminal A and HER2 positive tumors, but this is yet to be investigated.Trial registrationThe trial has been retrospectively registered at clinicaltrials.gov 2024-10-03 (NCT06637202).

Protocol for original SweBCG91RT trial

PURPOSE:Identifying biomarkers of radiotherapy (RT) response is important for optimizing the treatment of early breast cancer. In this study, we tested the interaction between endothelial cell (EC) expression of phospho-Tyr397-FAK (pY397-FAK) and adjuvant-RT on clinical outcomes after breast-conserving surgery (BCS) within a randomized study. Preclinical data suggest an enhanced effect of RT on low EC_pY397-FAK expression. EXPERIMENTAL DESIGN:We analyzed tissue microarrays from the Swedish Breast Cancer Group 91 Radiotherapy (stage I-II, lymph node-negative) breast cancer cohort, consisting of 1,178 patients randomly assigned to receive either BCS alone or BCS plus adjuvant-RT. Tissue microarray sections were immunostained for pY397-FAK, CD31, α-smooth muscle actin, and pan-cytokeratin. HALO analysis scored mean pY397-FAK intensity in CD31+ ECs, pan-cytokeratin-positive tumor epithelial cells, and α-smooth muscle actin + mural/stromal cells per core. For 822 patients, multivariable Cox regression analysis was performed for the primary and secondary 5-year endpoints, locoregional recurrence and all recurrence, respectively, as dependent variables and RT and EC_pY397-FAK as independent variables. RESULTS:EC_pY397-FAK expression was not predictive for the primary endpoint locoregional recurrence (P = 0.098), but the direction of the RT effect was in line with preclinical findings. For the secondary endpoint all recurrence, there was a significant interaction (P = 0.026) between EC_pY397-FAK and RT. Without RT, higher EC_pY397-FAK expression resulted in a lower risk for all recurrence (HR = 0.74 per SD; 95% confidence interval = 0.57-0.96; P = 0.026). CONCLUSIONS:Within the first 5 years following BCS, patients with low EC_pY397-FAK expression derive greater benefit from RT than patients with high EC_pY397-FAK expression. However, without RT, low EC_pY397-FAK expression is associated with a higher risk of recurrence.

Supplementary MethodsTable S5. Clinical characteristics of the Sjöström and Servant cohortsTable S6. Comparison of included versus excluded patientsTable S7. 10-year follow-up for local recurrence (IBTR). Flexible parametric survival analysis with Royston-Parmar (RP) regression models used in Figures 2 and 3Table S8. 10-year follow-up for local recurrence (IBTR). Flexible parametric survival analysis with Royston-Parmar (RP) regression models with adjustment for other covariatesTable S9. Absolute number of events within different tertiles of Immunescore and Proliferative Index and depending on RT treatmentTable S10. Unadjusted and adjusted analysis of the interaction between the Integrated model and RT in the SweBCG91RT cohortTable S11. Distribution of subtypes in the tertiles of the Integrated score among high-risk patients

BACKGROUND:There are currently no molecular tests to identify individual breast cancers where radiotherapy (RT) offers no benefit. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify low-risk cancers where RT will not further reduce recurrence rates. METHODS:An individual participant data meta-analysis was performed in 623 patients of node-negative estrogen receptor-positive and HER2-negative early breast cancer enrolled in 3 RT randomized trials for whom primary tumor material was available for analysis. A Cox proportional hazards model on time to locoregional recurrence was used to test the interaction between POLAR score and RT. RESULTS:A total of 429 (69%) patients' tumors had a high POLAR score, and 194 (31%) had a low score. Patients with high POLAR score had, in the absence of RT, a 10-year cumulative incidence of locoregional recurrence (20%, 95% confidence interval [CI] = 15% to 26%, vs 5%, [CI] 2% to 11%) for those with a low score. Patients with a high POLAR score had a large benefit from RT (hazard ratio [HR] for RT vs no RT = 0.37, 95% CI = 0.23 to 0.60; P < .001). In contrast, there was no evidence of benefit from RT for patients with a low POLAR score (HR = 0.92, 95% CI = 0.42 to 2.02; P = .832). The test for interaction between RT and POLAR was statistically significant (P = .022). CONCLUSIONS:POLAR is not only prognostic for locoregional recurrence but also predictive of benefit from RT in selected patients. Patients aged 50 years and older with estrogen receptor-positive and HER2-negative disease and a low POLAR score could consider omitting adjuvant RT. Further validation in contemporary clinical cohorts is required.

Gene sets from the molecular signatures database were used to create a model measuring immunological activity and immunomodulatory tumor-intrinsic factors. These were merged to create a model considering the interaction between the antitumoral immune response and tumor-intrinsic immunomodulatory factors.

Ki67 was evaluated by a board-certified pathologist on TMAs.

INTRODUCTION:Population-based registers provide an important source of real-world data. The growing number of large cohort studies using data from cancer registers makes validation of such registers important. The Swedish Quality Register of Gynecologic Cancer (SQRGC) is a nationwide population-based register containing data on patient and tumor characteristics, treatment, and follow-up. To ensure that the results from research and quality assurance reports using SQRGC data are robust and reliable, the accuracy and completeness of the register need to be validated. The aim of this study was to evaluate the quality of data on cervical cancer and vulvar cancer in the SQRGC. MATERIAL AND METHODS:Quality of data in the SQRGC was investigated by evaluating completeness, timeliness, comparability, and validity in accordance with recommendations from the International Agency for Research on Cancer and the national Swedish guidelines on validation of cancer registers. Completeness was evaluated by coverage relative to the Swedish National Cancer Register, and timeliness as the time from diagnosis until entry into the SQRGC. We randomly selected 276 women diagnosed with cervical cancer (n = 138) and vulvar cancer (n = 138) between 2014 and 2019 for validation. An external monitor manually re-abstracted data on 10 core variables per sub-register from the patients' medical records. Comparability was assessed by reviewing the adherence to international standards regarding coding. Validity was evaluated by the agreement between re-abstracted data and original data in the SQRGC. Correlations were estimated using Pearson's correlation coefficient and Cohen's kappa coefficient. RESULTS:For cervical cancer, the completeness was 99% and the timeliness was 87.1% within 12 months. The corresponding figures for vulvar cancer were 100% and 87.9%, respectively. Adherence to international coding standards was satisfactory. The median degree of agreement between re-abstracted data and data in the SQRGC was 90.8% (range 73.2%-100%) for cervical cancer, and 85.4% (range 59.6%-98.2%) for vulvar cancer. CONCLUSIONS:The data on cervical and vulvar cancer in the SQRGC are of adequate quality and may well be used for research and clinical purposes.

Supplementary Table S1 Demographics of the training cohortsSupplementary Table S2 Immunscore modelSupplementary Table S3 Proliferative Index ModelSupplementary Table S4 Immunescore:Proliferative Index

IntroductionEarly integration of palliative care (PC) alongside oncology care is widely recognised as beneficial for patients and their next of kin. Sharing the responsibility with colleagues can ease the burden for the physician. However, according to our previous research with physicians, while two out of three expressed a positive attitude towards early integration of PC, only one-third actually implemented it. To facilitate the early integration of PC, the physicians' own attitudes need to be highlighted. The aim of this study was to explore Swedish physicians' personal experiences and their view of the role of the organisation when referring patients with cancer to PC.MethodsA study was performed using a study-specific questionnaire. Physicians working with cancer patients within different specialties participated. Data were collected in a cross-sectional online survey. Quantitative data (items) were analysed using descriptive statistics and open-ended responses were analysed with thematic analysis.ResultsIn total, 130 physicians participated. The majority reported feeling confident when introducing PC to patients (97.6%) They expressed a high degree of medical and emotional relief when the patients were enrolled in PC. Organisational challenges were reported in gaining acceptance from PC providers (50.9%) and in ensuring equal access to PC (54.5%). Thematic analysis identified multifaceted aspects related to navigating barriers and facilitators in the referral process, the benefits achieved from mutual collaboration with PC providers, and the physician related challenges when managing the organisational labyrinth.ConclusionThe physicians expressed confidence in discussing PC with patients. They experienced personal, professional, patient-related and organisational benefits when patients were enrolled in PC. A majority expressed that the patients did not have equal access to PC. To reach this goal, organisational aspects, including communication pathways and geographical restrictions, need to be addressed.

Background/AimThe TGF-beta pathway can influence breast cancer progression and therapy efficacy, exhibiting both pro- and anti-tumoral effects. This study examined the impact of active TGF-beta signaling on recurrence and radiotherapy (RT) benefit in early-stage breast cancer, using nuclear phosphorylated Smad2 (pSMAD2) as a marker for pathway activation.MethodsTissue-microarrays from 1178 stage I-IIA breast cancer patients in the SweBCG91RT trial (randomized to breast-conserving surgery with or without RT) were analyzed. pSMAD2 immunohistochemistry was scored as the mean percentage of tumor cells with nuclear staining. Recurrence risk and RT benefit were evaluated.ResultspSMAD2 scores were heavily skewed, with 45% of tumors demonstrating high staining (>= 80% tumor cells), 38% medium (21-79%), and 17% low (<= 20%). Low pSMAD2 tumors were associated with higher grade and larger size but not with subtype. Medium pSMAD2 tumors had a significantly increased ipsilateral breast tumor recurrence risk than high pSMAD2 tumors (HRadjusted = 1.82, p = 0.002), while no differences were observed for low pSMAD2 tumors. A similar result was obtained with all recurrences as endpoint. RT benefit was consistent across all pSMAD2 groups. In Luminal tumors, higher tumoral pSMAD2 levels were inversely correlated with tumor-infiltrating lymphocytes (TILs).ConclusionMedium pSMAD2 levels were linked to an increased recurrence risk compared to high levels, suggesting a tumor-suppressive role of TGF-beta in early breast tumorigenesis. However, no significant differences were noted for low pSMAD2 levels. In Luminal tumors, TGF-beta signaling was negatively associated with TILs. These findings indicate that therapeutic targeting of TGF-beta warrants careful consideration of tumor stage and subtype.

The tumor-intrinsic model, Proliferative Index, could predict the prognostic effect from the immunological model, Immunescore. With high Proliferative Index values, Immunescore was strongly prognostic. However, with low Proliferative Index values, trends toward the opposite were observed.

Background and purpose: BRCA-related hormone receptor (HR)-negative breast cancers (BC) are reported to have aggressive tumor biology but also exhibit chemosensitivity. However, the impact of BRCA1/2 pathogenetic variants (PV) on BC outcomes remains unclear. This study compares survival outcomes for HR-negative BC between BRCA carriers and noncarriers. Patients/material and methods: From 489 female BRCA-carriers prospectively registered in western Sweden (1996–2017), those with primary HR-negative BC who underwent breast surgery until 2019 were included in the BRCA cohort. For each BRCA-carrier, three BRCA-noncarriers with HR-negative BC were matched based on age, time of diagnosis, and follow-up duration. Overall survival (OS) was analyzed using Kaplan‑Meier estimates and Cox proportional hazard ratios after adjustment for stage, chemotherapy, and surgical technique. A sensitivity analysis was performed to investigate the effect of HER2 status on HR-negative BC diagnosed after 2007. Results: Among the 106 BRCA carriers, 101 (95%) had a BRCA1 and 5 (5%) a BRCA2 PV. Most of the BRCA-carriers (89/106, 84%) were diagnosed with BC prior to genetic screening. Surgical techniques were similar between BRCA-carriers (n = 106) and noncarriers (n = 318). Chemotherapy was more common among BRCA-carriers (87% vs. 72%, p < 0.001). No significant difference in OS was found between BRCA-carriers and noncarriers among patients with HR-negative BC (adjusted HR: 0.81 [95% confidence interval [CI]: 0.43–1.53], p = 0.51) or considering HER2 status (adjusted HR 0.95 [95% CI: 0.43–2.07], p = 0.89). Interpretation: This study suggests that BRCA1/2 pathogenic variants do not independently impact survival outcomes in HR-negative BC. However, a moderate association between BRCA status and OS cannot be ruled out.

The interaction between the Integrated model and RT was significant in an unadjusted analysis (p=0.004) and an analysis adjusted for histological grade, age, ER status, and tumor size (p=0.008). The figure shows the predicted 10-year cumulative incidence of IBTR with 95% confidence intervals based on Integrated model score stratified by RT, based on Royston-Parmar models with estimates from Table S10. The stpm2 macro for Stata was used for the calculations. The dotted vertical lines represent percentiles of the Integrated score.

The immune system’s role in estrogen receptor (ER)-positive breast cancer is poorly understood. A population-based cohort of 428 breast cancer patients with clinical and molecular data was analyzed to assess how immune biomarkers can inform treatment decisions. Tumor-intrinsic immune responsiveness and local immune infiltration were quantified, and epithelial cell states were derived using EcoTyper. The interaction between ProliferativeIndex and Immunescore predicted risk of local recurrence in ER-positive tumors (HR 0.56, 95% CI 0.36–0.88, p = 0.012). EcoTyper identified two epithelial cell states, S04 and S05, with distinct immunomodulatory properties. S04 tumors showed higher proliferation, enrichment for M1 macrophages, CD8 effector T-cells, and plasma cells, alongside hypomethylation of immune-related pathways and hypermethylation of the PI3K signaling pathway. In contrast, S05-enriched tumors were associated with fibroblast activation, immune exclusion, and enrichment for glycosylation-related pathways. These findings suggest that epithelial cell states shape immune responsiveness in ER-positive breast cancer and may inform biomarker-driven treatment strategies.

Objective Population-based, organised prostate cancer testing (OPT) programmes were started in Sweden in 2020. The influence of socioeconomic factors on prostate cancer testing in this setting is not known. We examined associations between socioeconomic factors and (1) participation in OPT and (2) unorganised prostate-specific antigen (PSA) testing.Methods and analysis Region Västra Götaland’s OPT programme invited 21 174 men aged 50 years in 2020–2021. Regional data on unorganised testing in 2013–2014 of men aged 50–52 years were retrieved from Western Sweden Study of Opportunistic Prostate Cancer Screening database. Data on income, education, cohabitation and country of birth were collected from Statistic Sweden. Univariable and multivariable Poisson regression was used to calculate incidence rate ratios (IRRs) with CIs for PSA testing by socioeconomic category.Results Participation in OPT was associated with all investigated socioeconomic factors; multivariable IRRs: low versus non-low income 0.63 (95% CI 0.58 to 0.68), single versus non-single household 0.78 (95% CI 0.75 to 0.81), low versus average education 0.84 (95% CI 0.78 to 0.90) and non-Nordic versus Nordic country of birth 0.88 (95% CI 0.84 to 0.92). Unorganised PSA testing was negatively associated with low income 0.83 (95% CI 0.78 to 0.90) and single household 0.87 (95% CI 0.82 to 0.92), but not with low education 1.00 (95% CI 0.92 to 1.08) or non-Nordic country of birth 0.98 (95% CI 0.91 to 1.06).Conclusion Socioeconomic factors influenced PSA testing among 50-year-old men, both in an organised testing programme and in unorganised, clinical testing. An active offer of testing is not enough to achieve socioeconomic equality in the early detection of prostate cancer.

Lung transplantation (LTx) is a well-known treatment for end-stage lung disease. This study aimed to report the incidence of cancer after LTx and long-term outcome among lung transplant recipients with a pretransplant diagnosis of cancer. Patients who underwent LTx between 1990-2016 were included in the study. Detection of cancer was obtained by cross-checking the study population with the Swedish Cancer Registry and the Cause-of-Death registry. A total of 614 patients were followed for a median of 5.1 years. In all, 159 malignancies were diagnosed. The excess risk of cancer or standardized incidence ratio (SIR) following LTx was 5.6-fold compared to the general Swedish population. The most common malignancies were non-melanoma skin cancer (NMSC) (SIR 76.5 (95%CI 61.7-94.8); non-Hodgkin lymphoma (SIR 23.5, 95%CI 14.8-37.2); and lung cancer (SIR 8.89, 95%CI 5.67-13.9). There was no significant difference in overall survival between those with and without a history of cancer before LTx (p = 0.56). In total, 159 malignancies were identified after LTx, which was a 5.6-fold higher relative to the general population. A history of previous cancer yields similar survival in selected recipients, compared to those without cancer prior to LTx.