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Purpose: The local immune infiltrate's influence on tumor progression may be closely linked to tumor-intrinsic factors. The study aimed to investigate whether integrating immunologic and tumor-intrinsic factors can identify patients from a low-risk cohort who may be candidates for radiotherapy (RT) de-escalation. Experimental Design: The SweBCG91RT trial included 1,178 patients with stage I to IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median of 15.2 years. We trained two models designed to capture immunologic activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could further stratify tumors, allowing for identifying a subgroup where RT de-escalation is feasible, despite clinical indicators of a high risk of ipsilateral breast tumor recurrence (IBTR). Results: The prognostic effect of the immunologic model could be predicted by the tumor-intrinsic model (Pinteraction = 0.01). By integrating measurements of the immunologic- and tumor-intrinsic models, patients who benefited from an active immune infiltrate could be identified. These patients benefited from standard RT (HR, 0.28; 95% CI, 0.09–0.85; P = 0.025) and had a 5.4% 10-year incidence of IBTR after irradiation despite high-risk genomic indicators and a low frequency of systemic therapy. In contrast, high-risk tumors without an immune infiltrate had a high 10-year incidence of IBTR despite RT treatment (19.5%; 95% CI, 12.2–30.3). Conclusions: Integrating tumor-intrinsic and immunologic factors may identify immunogenic tumors in early-stage breast cancer populations dominated by ER-positive tumors. Patients who benefit from an activated immune infiltrate may be candidates for RT de-escalation.

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

Purpose:The local immune infiltrate's influence on tumor progression may be closely linked to tumor-intrinsic factors. The study aimed to investigate whether integrating immunologic and tumor-intrinsic factors can identify patients from a low-risk cohort who may be candidates for radiotherapy (RT) de-escalation.Experimental Design:The SweBCG91RT trial included 1,178 patients with stage I to IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median of 15.2 years. We trained two models designed to capture immunologic activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could further stratify tumors, allowing for identifying a subgroup where RT de-escalation is feasible, despite clinical indicators of a high risk of ipsilateral breast tumor recurrence (IBTR).Results:The prognostic effect of the immunologic model could be predicted by the tumor-intrinsic model (Pinteraction = 0.01). By integrating measurements of the immunologic- and tumor-intrinsic models, patients who benefited from an active immune infiltrate could be identified. These patients benefited from standard RT (HR, 0.28; 95% CI, 0.09–0.85; P = 0.025) and had a 5.4% 10-year incidence of IBTR after irradiation despite high-risk genomic indicators and a low frequency of systemic therapy. In contrast, high-risk tumors without an immune infiltrate had a high 10-year incidence of IBTR despite RT treatment (19.5%; 95% CI, 12.2–30.3).Conclusions:Integrating tumor-intrinsic and immunologic factors may identify immunogenic tumors in early-stage breast cancer populations dominated by ER-positive tumors. Patients who benefit from an activated immune infiltrate may be candidates for RT de-escalation.

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

Protocol for original SweBCG91RT trial

Study protocol

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 (P = 0.039 and P = 0.035) and was also significant for ipsilateral breast tumor recurrence in the gene expression analyses (P = 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.

BackgroundThe implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT.MethodsThe SweBCG91RT trial included 1178 patients with stage I–IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. Immunohistochemical analyses of TILs, PD-1, and PD-L1 were performed. An activated immune response was defined as stromal TILs ≥10% and PD-1 and/or PD-L1 expression in ≥1% of lymphocytes. Tumors were categorized as high-risk or low-risk using assessments of histological grade and proliferation as measured by gene expression. The risk of ipsilateral breast tumor recurrence (IBTR) and benefit of RT were then analyzed with 10 years follow-up based on the integration of immune activation and tumor-intrinsic risk group.ResultsAmong high-risk tumors, an activated immune infiltrate was associated with a reduced risk of IBTR (HR 0.34, 95% CI 0.16 to 0.73, p=0.006). The incidence of IBTR in this group was 12.1% (5.6–25.0) without RT and 4.4% (1.1–16.3) with RT. In contrast, the incidence of IBTR in the high-risk group without an activated immune infiltrate was 29.6% (21.4–40.2) without RT and 12.8% (6.6–23.9) with RT. Among low-risk tumors, no evidence of a favorable prognostic effect of an activated immune infiltrate was seen (HR 2.0, 95% CI 0.87 to 4.6, p=0.100).ConclusionsIntegrating histological grade and immunological biomarkers can identify tumors with aggressive characteristics but a low risk of IBTR despite a lack of RT boost and systemic therapy. Among high-risk tumors, the risk reduction of IBTR conferred by an activated immune infiltrate is comparable to treatment with RT. These findings may apply to cohorts dominated by estrogen receptor-positive tumors.

We investigated the importance of HGF, pMET and pAkt for the risk of ipsilateral breast tumour recurrence after adjuvant radiotherapy in primary breast cancer in tumours from the SweBCG91‐RT randomised trial. Low levels of HGF and pMet in the tumour cell cytoplasm and high levels of pAkt in the tumour cell nucleus are associated with a larger benefit from RT, indicating that these proteins may be used as biomarkers or treatment targets., 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 (HGFstr); pMet in the membrane (pMetmem); HGF, pMet and pAkt in the cytoplasm (HGFcyt, pMetcyt, pAktcyt); and pAkt in the nucleus (pAktnuc). 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 HGFcyt and pMetcyt and high levels of pAktnuc 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 HGFcyt and pMetcyt, and low pAktnuc [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 HGFcyt, low pMetcyt and high pAktnuc may derive an increased benefit from RT after breast‐conserving surgery concerning the risk of developing IBTR.

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 Dmean (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 Dmean 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.

Introduction: Over the last few years, neoadjuvant therapy has become a standard of care in HER2-positive early breast cancer. This standard has recently been confirmed by the St. Gallen Consensus for stage II and III HER2-positive disease. In neoadjuvant treatment adding anti HER2 treatment almost doubled the pathological complete response (pCR) rate. Later studies have shown a better outcome for patients achieving a pCR compared with those with a non-pCR. The aim of this study is to present a comprehensive description of preoperative treatment in HER2-positive, according to ASCO and Swedish guidelines, breast cancer with detail treatment routines, choice of drugs and regimens as well as adherence to national guidelines and treatment changes over time. Material: During the period October 2010 to December 2017 6572 patients with early breast cancer were diagnosed in the Skåne region of South Sweden and included in the SCAN-B project (Sweden Cancerome Analysis Network - Breast project, ClinicalTrials.gov identifier NCT02306096). The SCAN-B project is a population based study that during the period included 76.7% of all primary breast cancer patients in the catchment area. The majority of all tumors have been analyzed by NGS-based RNA sequencing, RNAseq. Results: Of the 6572 patients 672 (10.2%) were HER2 positive and of these 101 (15%) were treated in a neoadjuvant setting with chemotherapy and HER2 directed antibodies. The proportion of HER2-positive patients receiving neoadjuvant treatment with trastuzumab increased from 9% in 2010 to 29% in 2017. Patient age was 27 to 89 years, median age 54 years. Pertuzumab was introduced in 2016 and in 2017 85% of patients received the combination of trastuzumab and pertuzumab. At diagnosis tumor stage T1, T2, T3 and T4d was 19%, 60%, 14% and 5% respectively and 50% were node negative at sentinel node biopsy pre treatment. Of tumors 52% were estrogen receptor positive (ie >10% stained nuclei). During the neoadjuvant treatment period 31 patients were hospitalized at median 2 times for toxicity and a total of medium 4.7 days. At surgery 62% had a mastectomy and 38% breast conserving surgery. Follow up time is median 3.9 years and overall survival 94%. Conclusions: This retrospective analysis of neoadjuvant treated HER2-positive breast cancer patients shows a gradual increase of neoadjuvant treatment and a very fast implementation of pertuzumab when it became available in Sweden. Overall survival is high but the follow up time is short and the material to small to analyze subgroups. Data on tumor RNAseq will be presented. Citation Format: Martin Malmberg, Christer Larsson, Johan Vallon-Christersson, Anna Ehinger, Cecilia Hegardt, Fredrika Killander, Lisa Ryden, Lao H. Saal, Niklas Loman, Åke Borg. Preoperative treatment of HER2-positive breast cancer in South Sweden. A retrospective, comprehensive survey of neo-adjuvant treated HER2-positve breast cancer in the SCAN-B project 2010-2017 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-10.

Purpose: The effect of postoperative radiotherapy (RT) based on the immune phenotype of tumor-infiltrating lymphocytes (TILs) has not been investigated. The purpose of this study was to analyze how the balance between CD8+ T cells and T regulatory cells (FOXP3+), which have opposite effects on the anti-tumoral defense, affects the risk of ipsilateral breast tumor recurrence (IBTR) and of any recurrence as well as the interaction with RT in a large randomized RT trial. Methods: In the SweBCG91RT trial, patients with breast cancer stage I and II were randomized to breast conserving surgery (BCS) and postoperative RT or BCS only and followed for a median time of 15.2 years. Tumor blocks were retrieved and stromal TILs were assessed through hematoxylin-eosin stained slides. CD8+ T cells and T regulatory cells were evaluated through staining for CD8 and FOXP3 and the percentage of stroma occupied by CD8+ T cells and T regulatory cells respectively was then calculated. Cutoffs at 5% and 2.5% were used to define high levels of CD8+ T cells (CD8High) and T regulatory cells (FOXP3High), respectively. In total, 943 patients were analyzed. Results: Among patients who did not receive RT, an increased risk of IBTR and of any recurrence was seen in the CD8Low/FOXP3Low (HR 2.64, CI95% 1.26-5.56, p=0.010 and HR 2.52, CI95% 1.34-4.77, p=0.004, respectively) and CD8High/FOXP3High (HR 1.94, CI95% 0.81-4.63, p=0.135 and HR 2.76, CI95% 1.36-5.57, p=0.005, respectively) groups compared to CD8High/FOXP3Low (HR 1.0) in multivariable analyses including grade and age. The effect of RT on risk of IBTR was more pronounced in the groups with CD8Low/FOXP3Low (HR 0.37, CI95% 0.24-0.57, p Conclusions: Our findings suggest that patients with a favorable immune phenotype (CD8High/FOXP3Low) may not derive any benefit from adjuvant RT which could be explained by an interaction through which RT may suppress an activated immune response. These results may have an impact on decisions regarding postoperative RT in early breast cancer. Citation Format: Axel Stenmark Tullberg, Henri AJ Puttonen, Erik Holmberg, Dan Lundstedt, Fredrika Killander, Emma Niméus, Anikó Kóvacs, Per Karlsson. A high ratio of CD8/FOXP3 predicts an unfavorable response to postoperative radiotherapy after breast-conserving surgery: Results from the randomized SweBCG91RT trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-10.

Breast-conserving surgery followed by radiotherapy is part of standard treatment for early-stage breast cancer. Hypoxia is common in cancer and may affect the benefit of radiotherapy. Cells adapt to hypoxic stress largely via the transcriptional activity of hypoxia-inducible factor (HIF)-1α. Here, we aim to determine whether tumour HIF-1α-positivity and hypoxic gene-expression signatures associated with the benefit of radiotherapy, and outcome.Tumour HIF-1α-status and expression of hypoxic gene signatures were retrospectively analysed in a clinical trial where 1178 women with primary T1-2N0M0 breast cancer were randomised to receive postoperative radiotherapy or not and followed 15 years for recurrence and 20 years for breast cancer death.The benefit from radiotherapy was similar in patients with HIF-1α-positive and -negative primary tumours. Both ipsilateral and any breast cancer recurrence were more frequent in women with HIF-1α-positive primary tumours (hazard ratio, HRThe benefit of postoperative radiotherapy persisted in patients with hypoxic primary tumours. Patients with hypoxic primary breast tumours had an increased risk of recurrence and breast cancer death.

Background: Adjuvant locoregional radiotherapy (LRRT) reduces risk of locoregional failures (LRF) and improves survival for node positive breast cancer (BC) patients. However, LRRT increases the risk for toxicity as edema in the arm, lung cancer and cardiac mortality. Modern radiotherapy allows a more conform therapy which makes knowledge of LRF-patterns very important, in order not to underdose volumes with high risk for microscopic disease and simultaneously restrict dose to risk organs. In addition, BC-subtype may affect radiosensitivity and could possibly be used to individualize LRRT in the future. Methods: We investigated outcome for BC-patients receiving LRRT in the Southwest Sweden (2004-2008) in order to identify LRFs. During this period patients with >3 positive lymph nodes were given LRRT (50Gy in 2Gy fractions) to the breast/thoracic wall, axilla level II+III, supra- and infraclavicular lymph nodes according to a target definition atlas introduced in 2002. Patients with LRF as first event were identified, with distant failures and death considered as competing risks. The anatomical distribution of LRF was compared with the contouring atlas, radiotherapy given, and biological subtype based on immunohistochemistry. Results: 904 patients received LRRT. Median follow-up time was 9.8 years (0.2-14.6) for patients without an event. 59 patients (6,5%) developed a LRF, 30 of which were local failures (LF) and 31 regional failures (RF) (2 simultaneous LF/RF). Median time to LRF was 2.8 years. 37 of the 59 (63%) LRF-patients developed generalized disease within 3 months from the LRF. Of the 845 patients without LRF 316 developed distant metastases as first recurrence, 1 an isolated RF in the contralateral axilla, 64 died from other causes, and for 5 patients recurrence-status was unclear. 459 were alive at end of follow-up. Of the LF 19 developed after mastectomy (MRM) and 11 after breast conserving surgery (BCS). LF-location after MRM: 9 in-field, 6 at field margin, 2 both in/out of field, 1 out of field, and for 1 not yet determined. After BCS: 8 in-field, 1 at field margin, and for 2 not yet determined. Of the RF 28 developed after MRM and 3 after BCS. Location of RF after MRM: 11 in-field, 6 at field margin, 1 both in/out of field, 2 out of field, and for 8 not yet determined. After BCS: 1 in-field, 1 at field margin, and 1 not yet determined. The most common location for RF close to /out of field was superior to the treated area in fossa supraclavicularis. Biological approximate subtype was available for 885 of the primary tumours; luminal (ER+ and/or PR+ HER2-/?) 67% (589/885), HER2+ 19% (169/885), triple negative (ER- and PR- HER2-/?) (TN) 14% (127/885). Subtype distribution of BC later causing LRF despite LRRT was: luminal 44% (26/59), HER2+ 27% (16/59), TN 29% (17/59). Among primary tumours causing a LRF within irradiated volume 77% (24/31) were HER2+ or TN. Conclusion: In this high risk cohort of BC-patients, we found a low incidence of LRFs. The majority of LRFs developed within irradiated volume. BCs of the HER2+ and TN-subtype may be more radioresistant and have a higher risk of LRF. Updated information as well as figures mapping all recurrences in relation to previous LRRT will be presented at the symposium. Citation Format: Adra J, Karlsson P, Killander F, Lundstedt D, Alkner S. Distribution of locoregional breast cancer recurrences in relation to previous radiotherapy and biological subtype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD8-11.

BackgroundPrognostic factors in breast cancer are often measured on a continuous scale, but categorized for clinical decision-making. The primary aim of this study was to evaluate if accounting for continuous non-linear effects of the three factors age at diagnosis, tumor size, and number of positive lymph nodes improves prognostication. These factors will most likely be included in the management of breast cancer patients also in the future, after an expected implementation of gene expression profiling for adjuvant treatment decision-making.MethodsFour thousand four hundred forty seven and 1132 women with primary breast cancer constituted the derivation and validation set, respectively. Potential non-linear effects on the log hazard of distant recurrences of the three factors were evaluated during 10years of follow-up. Cox-models of successively increasing complexity: dichotomized predictors, predictors categorized into three or four groups, and predictors transformed using fractional polynomials (FPs) or restricted cubic splines (RCS), were used. Predictive performance was evaluated by Harrells C-index.ResultsUsing FP-transformations, non-linear effects were detected for tumor size and number of positive lymph nodes in univariable analyses. For age, non-linear transformations did, however, not improve the model fit significantly compared to the linear identity transformation. As expected, the C-index increased with increasing model complexity for multivariable models including the three factors. By allowing more than one cut-point per factor, the C-index increased from 0.628 to 0.674. The additional gain, as measured by the C-index, when using FP- or RCS-transformations was modest (0.695 and 0.696, respectively). The corresponding C-indices for these four models in the validation set, based on the same transformations and parameter estimates from the derivation set, were 0.675, 0.700, 0.706, and 0.701.ConclusionsCategorization of each factor into three to four groups was found to improve prognostication compared to dichotomization. The additional gain by allowing continuous non-linear effects modeled by FPs or RCS was modest. However, the continuous nature of these transformations has the advantage of making it possible to form risk groups of any size. Funding Agencies|Swedish Cancer Society; Swedish Research Council; Gunnar Nilsson Cancer Foundation; Swedish Breast Cancer Association; Swedish Cancer and Allergy Foundation; Mrs. Berta Kamprad Foundation; Anna and Edwin Bergers Foundation; Skane County Councils Research and Development Foundation; Governmental Funding of Clinical Research within the National Health Service

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.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 CD8An 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 (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.

This study shows that immunosuppressive primary breast cancer patient–derived G-MDSCs (PMN-MDSCs) are neutrophils at a range of maturations stages, and provides in vivo evidence for that human G-MDSCs also promote tumor growth and myeloid immune cell exclusion., Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.

Introduction Breast conserving surgery (BCS) with postoperative radiotherapy (RT) is recommended for the majority of patients with early breast cancer. Meta-analyses of randomized trials have shown reduction of breast cancer and overall mortality after RT but increased cardiovascular mortality Aim To evaluate side effects of RT after BCS Patients and Methods Trial SweBCG 91RT randomized 1187 women with stage 1-IIA breast cancer after BCS to RT or to no further treatment. RT was administered as tangential opposing beams to the breast to a target dose of 48-54 Gy. Three-dimensional dose planning on multiple CT slices 10 mm apartwas used for 69% of the patients and for the remainder two-dimensional planning. All hospital records and radiotherapy charts were monitored. Update of mortality, cause of death and morbidity was made using the Swedish personal identification numbers and the following Swedish national registers: the Cancer Register, the Population Register, the Cause of Death Register, the Inpatient and the SWEDEHEART registers. For analyses the diagnoses were grouped as follows: breast cancer, cardiovascular disease, cerebrovascular disease, lung cancer and benign pulmonary disease Statistics Overall mortality was calculated using the Kaplan-Meier method, whereas cumulative incidence functions with other causes of death as competing events were used for cause-specific mortality and morbidities. For all outcomes, log-rank tests were used to compare between treatment groups up to 20 years. We studied two populations: 1) patients according to intention to treat for overall and breast cancer mortality and 2) patients treated per protocol for side effects. Cause-specific death was allocated to a certain group when either the underlying or a contributing cause belonged to the disease group Results After 20 years, overall mortality was 42.9% after BCS and 42.5% after BCS+RT (p=0.8), and breast cancer mortality was 18.0% vs 15.8% (p=0.3). The cumulative incidence of mortality from heart disease was 12.4% after BCS and 13.0% after BCS+RT (p=0.8) with no difference for left or right side. Ischemic heart disease and congestive heart failure were the most common cardiac diagnoses. The cumulative incidence of cerebrovascular mortality was 3.4% among controls and 6.7% after RT (p=0.016). Of the patients with cerebrovascular death, 50% also had a cardiac cause of death. Other cause-specific mortalities investigated were similar regardless of RT: lung cancer 1.7% vs 1.9% (p=1.0), benign pulmonary disease 7.1% vs 6.4% (p=0.5) Morbidity Morbidity outcomes were also similar in control and irradiated patients: the cumulative incidence of hospital admissions with cardiac diagnoses 29.7% vs 31.0% (p=0.7), and for cerebrovascular morbidity 11.6% vs 13.7% (p= 0.33) respectively Radiation exposure The original dose plans were retrieved from 125 patients. Doses to organs at risk were recalculated. Median of mean heart dose was 3.0 Gy (1.1-8.2) for left and 1.0 Gy (0.5-2.5) for right-sided RT Conclusions After 20 years tangential RT in a randomized trial was not associated with increased cardiac mortality. A minor increase in cerebrovascular mortality was seen, but the causality is unclear. Citation Format: Malmström P, Karlsson P, Holmberg E, Lundstedt D, Holmberg L, Werner-Hartman L, Koul S, Kjellén E, Killander F. No increased cardiovascular mortality after twenty years in a randomized trial of radiotherapy after breast conserving surgery, SweBCG 91RT, from the Swedish breast cancer group [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD8-10.

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.

546 Background: The antitumoral immune response is dynamic and changes with tumor progression. Previous studies show that immunohistochemical (IHC) assessment of TILs in local recurrences can predict prognosis. It is not clear how adjuvant radiotherapy (RT) can alter the local immune response or if gene expression analyses of TILs in recurrences can provide prognostic information. Methods: Matched biopsies from primary tumors and ipsilateral breast tumor recurrences (IBTRs) from the randomized SweBCG91RT trial were assessed for TILs. Analyses were performed using gene expression (86 matched pairs) and IHC assessment (126 matched pairs). Results: The median time to IBTR was 8.0 years among irradiated patients and 3.6 years among unirradiated patients. In the gene expression analyses, higher absolute values of CD8+ T cells, CD4+ effector memory and CD8+ effector memory T cells in the recurrence could significantly predict a decreased risk of subsequent distant metastasis. In addition, a net increase of these cells in the IBTR compared to the primary tumor was associated with a significantly lower risk of metastasis. TILs did not change significantly between the matched tumors for the whole group or among irradiated patients versus unirradiated patients in the gene expression or IHC analyses. Surprisingly, the group with unchanged TILs levels as measured by IHC had the lowest risk of metastasis while an increase or a decrease in TILs was significantly associated with an increased risk. Conclusions: Cytotoxic and memory T cells in the recurrence protect against subsequent distant metastasis although IHC measurement of TILs could not confirm these results. No significant differences in TILs infiltration between irradiated versus unirradiated patients could be determined in the recurrences. Further analyses including changes of subtypes between the primary tumor and the recurrence will be presented.

TPS605 Background: Neo-adjuvant systemic therapy (NAT) is the standard of care for most patients with early HER2-amplified and triple negative breast cancer (BC). Increasing the rate of pathological complete response (pCR) is highly meaningful for those patients, as pCR is strongly predictive for improved long-term disease-related outcomes. Clinical and preclinical evidence support the hypothesis that pCR-rates may be augmented by the addition of checkpoint inhibitors, such as monoclonal antibodies targeting the Programmed Death Ligand receptor 1 (PD-L1), to standard systemic NAT. Studies in different BC patient cohorts (e.g., IMPassion130, PANACEA, KATE2) have indicated that PD-L1 protein expression on tumor-infiltrating lymphocytes (TIL’s) is a predictive marker for checkpoint inhibitor efficacy. Methods: We have initiated a phase II open-label, 2:1 randomized clinical trial where women with early HER2-amplified, PD-L1+ BC (cT2-3 and/or cN+) are treated with standard NAT (composed of anti-HER2 antibodies with a chemotherapy backbone of sequentially taxanes + carboplatin and epirubicin + cyclophosphamide [EC]) +/- atezolizumab during EC. N = 190 patients will be accrued in nine centers in Sweden to be able to demonstrate a 20% increase in pCR-rate, with a power of 80% and a two-sided alpha of 10%. Firstly, a prescreening is performed to select patients with a PD-L1 expression of > 1% on TIL’s. Important exclusion criteria are significant organ dysfunction and (with some exceptions) active auto-immune diseases. Extensive translational side-studies are performed to explore predictive markers for treatment efficacy, including clinicopathologic studies, molecular imaging and microbiome analyses, as well as monitoring of acute and chronic treatment-related toxicity, objective cognitive function and quality of life. As of February 11th, 4 patients have been prescreened and 1 enrolled in the trial. The clinical trial registry number is NCT03894007. Clinical trial information: NCT03894007 .

MDSCs are potent immunosuppressive myeloid cells that have been implicated in various diseases, including cancer. In humans, MDSCs are divided into Mo-GMDSCs and G-MDSCs subgroups, depending on their surface phenotype and function. While their immunosuppressive properties have been extensively studied, knowledge about their origin and their tumor-promoting functions per se remains scarce. In this study, we demonstrate that G-MDSCs are significantly enriched in the peripheral blood of locoregional recurrent metastatic breast cancer (LRR/MBC) compared to healthy donors. The G-MDSCs display a heterogeneous population with a morphology representing one blast-like and one polymorphonuclear (PMN) population. In a breast cancer xenograft model, co-transplanting G-MDSCs sorted from LRR/MBC together with breast cancer cells significantly promoted angiogenesis and tumor growth. Gene expression profiling analysis revealed that G-MDSCs from LRR/MBC rather clustered with neutrophils from healthy donors, sharing similar expression in genes relevant for angiogenesis, lymphangiogenesis and immunosuppression, but surprisingly not with G-MDSCs from sepsis patients. We conclude that enrichment of G-MDSCs in metastatic breast cancer represents a heterogeneous population of activated neutrophils that can promote angiogenesis and tumor progression, and immature blasts of yet unknown character. Citation Format: Meliha Mehmeti, Caroline Bergenfelz, Daniel Bexell, Robert Carlsson, Rebecka Hellsten, Anna-Maria Larsson, Niklas Loman, Kristian Riesbeck, Jonas Ahl, Camilla Rydberg-Millrud, Gesine Paul-Visse, Lisa Rydén, Fredrika Killander, Karin Leandersson. Human granulocytic myeloid-derived suppressor cells (G-MDSCs) in metastatic breast cancer patients is a heterogeneous population with angiogenic potential in vivo [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A73.

Purpose: The aim of this study was to verify if radiotherapy (RT) safely can be omitted in older women treated for estrogen-receptor positive early breast cancer with breast-conserving surgery (BCS) and endocrine therapy (ET). Patients and Methods: Eligibility criteria were: consecutive patients with age >= 65 years, BCS + sentinel node biopsy, clear margins, unifocal T1N0M0 breast cancer tumor, Elston-Ellis histological grade 1 or 2 and estrogen receptor-positive tumor. After informed consent, adjuvant ET for 5 years was prescribed. Primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were contralateral breast cancer and overall survival. Results: Between 2006 and 2012, 603 women were included from 14 Swedish centers. Median age was 71.1 years (range 65-90). After a median follow-up of 68 months 16 IBTR (cumulative incidence at five-year follow-up; 1.2%, 95% CI, 0.6% to 2.5%), 6 regional recurrences (one combined with IBTR), 2 distant recurrences (both without IBTR or regional recurrence) and 13 contralateral breast cancers were observed. There were 48 deaths. One death (2.1%) was due to breast cancer and 13 (27.1%) were due to other cancers (2 endometrial cancers). Five-year overall survival was 93.0% (95% CI, 90.5% to 94.9%). Conclusion: BCS and ET without RT seem to be a safe treatment option in women >= 65 years with early breast cancer and favorable histopathology. The risk of IBTR is comparable to the risk of contralateral breast cancer. Moreover, concurrent morbidity dominates over breast cancer as leading cause of death in this cohort with low-risk breast tumors. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Purpose To evaluate the effect of adjuvant radiotherapy (RT) after breast conservation surgery in different breast cancer subtypes in a large, randomized clinical trial with long-term follow-up. Patients and Methods Tumor tissue was collected from 1,003 patients with node-negative, stage I and II breast cancer who were randomly assigned in the Swedish Breast Cancer Group 91 Radiotherapy trial between 1991 and 1997 to breast conservation surgery with or without RT. Systemic adjuvant treatment was sparsely used (8%). Subtyping was performed with immunohistochemistry and in situ hybridization on tissue microarrays for 958 tumors. Results RT reduced the cumulative incidence of ipsilateral breast tumor recurrence (IBTR) as a first event within 10 years for luminal A-like tumors (19% v 9%; P = .001), luminal B-like tumors (24% v 8%; P.001), and triple-negative tumors (21% v 6%; P = .08), but not for human epidermal growth factor receptor 2-positive (luminal and nonluminal) tumors (15% v 19%; P = .6); however, evidence of an overall difference in RT effect between subtypes was weak ( P = .21). RT reduced the rate of death from breast cancer (BCD) for triple-negative tumors (hazard ratio, 0.35; P = .06), but not for other subtypes. Death from any cause was not improved by RT in any subtype. A hypothesized clinical low-risk group did not have a low risk of IBTR without RT, and RT reduced the rate of IBTR as a first event after 10 years (20% v 6%; P = .008), but had no effect on BCD or death from any cause. Conclusion Subtype was not predictive of response to RT, although, in our study, human epidermal growth factor receptor 2-positive tumors seemed to be most radioresistant, whereas triple-negative tumors had the largest effect on BCD. The effect of RT in the presumed low-risk luminal A-like tumors was excellent.

Aim To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Methods Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. Results In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. Conclusion SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC.

To analyse late morbidity and mortality in pre and post-menopausal breast cancer patients treated with postmastectomy radiotherapy, with emphasis on side-effects from the heart, cerebrovascular and respiratory systems.Long term follow-up of two randomised, clinical trials with 1100 patients was carried out. Pre-menopausal women were allocated to radiotherapy (RT), RT+oral cyclophosphamide (RT+C) or cyclophosphamide only (C). Post-menopausal women were allocated to RT, RT+Tamoxifen for one year (RT+Tam) or tamoxifen only (Tam). Information on admission to hospital, mortality and causes of death was obtained from national registers.After 25 years, adding RT to cyclophosphamide in pre-menopausal women raised the mortality from heart disease from zero to 0.8% (p=0.04). In post-menopausal women, adding RT to Tam raised the mortality from heart disease from 10.5% to 18.4% (p=0.005). In post-menopausal women mortality due to cerebrovascular disease increased from 3.4% to 8.7% by adding RT to Tam (p=0.015). The differences were not evident until in the second decade of follow-up. In spite of differences in specific causes of death, there were no significant differences between the treatment arms concerning morbidity or overall mortality.Postmastectomy radiotherapy to the chest wall and loco-regional lymph nodes including the parasternal lymph nodes as delivered in the end of the seventies did not reduce overall mortality, but gave a significantly increased risk of death from heart and cerebrovascular disease, which appeared during the second decade after radiotherapy.

Breast cancer is the most common cancer form in women and it has been extensively studied on the molecular level. Male breast cancer (MBC), on the other hand, is rare and has not been thoroughly investigated in terms of transcriptional profiles or genomic aberrations. Most of our understanding of MBC has therefore been extrapolated from knowledge of female breast cancer. Although differences in addition to similarities with female breast cancer have been reported, the same prognostic and predictive markers are used to determine optimal management strategies for both men and women diagnosed with breast cancer. This review is focused on prognosis for MBC patients, prognostic and predictive factors and molecular subgrouping; comparisons are made with female breast cancer. Information was collected from relevant literature on both male and female breast cancer from the MEDLINE database between 1992 and 2014.MBC is a heterogeneous disease, and on the molecular level many differences compared to female breast cancer have recently been revealed. Two distinct subgroups of MBC, luminal M1 and luminal M2, have been identified which differ from the well-established intrinsic subtypes of breast cancer in women. These novel subgroups of breast cancer therefore appear unique to MBC. Furthermore, several studies report inferior survival for men diagnosed with breast cancer compared to women. New promising prognostic biomarkers for MBC (e.g. NAT1) deserving further attention are reviewed. Further prospective studies aimed at validating the novel subgroups and recently proposed biomarkers for MBC are warranted to provide the basis for optimal patient management in this era of personalized medicine.This article is part of a Directed Issue entitled: Rare Cancers.

Breast-conserving surgery (BCS) followed by radiotherapy (RT) is an established treatment for women with T1-2N0 breast cancers. Since subgroups of patients have low ipsilateral breast tumour recurrence (IBTR) rates, it is important to study whether RT is necessary for all patients.A total of 1187 women with primary T1-2N0M0 breast cancer were randomised, after standardised sector resection, to postoperative whole breast RT or no local treatment. Adjuvant systemic therapy was offered to patients with stage II cancers. Patients were followed with clinical examinations and annual mammography for 10 years and thereafter referred to the Swedish mammography screening program.After 15 years of follow-up, a higher cumulative incidence of IBTR was observed in control patients, 23.9%, versus irradiated patients, 11.5%, P0.001. Recurrence-free survival was inferior, 51.7% versus 60.4%, P=0.0013. The main effect of RT was seen during the first 5 years. However, overall survival was not significantly lower 68.4% versus 71.1%, P=0.68, nor was breast cancer-specific mortality significantly higher.RT after BCS significantly reduced the incidence of IBTR at 15 years of follow-up. We were unable to identify subgroups which could be spared RT. Breast cancer mortality was not significantly reduced after RT. Good predictive markers for radiation sensitivity and improved adjuvant systemic therapy are needed to omit RT after BCS.

Background: Postoperative radiotherapy remains the golden standard after breast conservation surgery. However, national breast screening programmes and increased public awareness of breast cancer have resulted in earlier detection of small tumours with favourable prognosis. The Swedish SweBCG 91RT multicentre study of breast conservation with and without radiotherapy was initiated in 1991. Five year results have been published.(Malmström P et al. Eur J Cancer 39: 1690, 2003). A gene expression signature for radioresistance has also been defined from this patient material. (Niméus-Malmström E et al. Breast Cancer Res 2008, 10:R3(doi10:1186/brc1997). Increasing knowledge of genetically defined subgroups of breast cancer is likely to have an impact on breast conservation treatment. We now present outcome after 15 years of follow-up. Patients and methods: After a standardised radical sector resection 1187 patients with T1-2N0M0 breast cancer were randomised to postoperative radiotherapy or no further treatment. 1178 patients fulfilled the inclusion criteria. The two treatment groups were well balanced with respect to prognostic factors. Median tumour size was 12 mm, and 65 % of cases were detected by mammography screening. Radiotherapy with tangential MV photons, 48-54 Gy in 24-27 fractions, was administered to the remaining breast parenchyma. CT-based 3-D treatment planning was used. Adjuvant systemic therapy was prescribed according to regional treatment programmes. Nine percent received adjuvant systemic therapy. Patients were followed annually with bilateral mammography for 10 years and thereafter referred to the national Swedish breast screening programme. Results: With a median follow-up of 15 years, the addition of postoperative radiotherapy did not affect overall survival, 70.8 % with RT vs 68.2 % without RT, p=0.79. This result is based on follow-up for survival until April 2010 for all patients. However, recurrence-free survival, RFS, was significantly improved by radiotherapy, 62,6 % vs 53.7 % after 15 years, P Conclusions: Postoperative breast radiotherapy is indicated for the majority of patients operated with breast conservation surgery. Analysis of treatment efficacy in subgroups of patients may identify groups for which radiotherapy can be omitted in the future. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-03.

Background: The importance of radiotherapy for local control after mastectomy and breast conservation surgery is well established with a reduction in loco-regional recurrences by two thirds. In early radiotherapy trials the reduction of loco-regional failures did not result in a reduction of mortality due to increased late non-breast cancer mortality. The 2005 overview of radiotherapy by EBCTCG did however show a significantly improved survival with the addition of radiotherapy. Patients and methods: From 1978 to 1985 1100 patients with breast cancer stage II were included in two randomized trials of radiotherapy and adjuvant systemic treatment, SBII:1 pre (Cyclophosphamide per os one year) and SB II:1 post (Tamoxifen 10 mg x 3 one year). The radiotherapy technique and the outcome of these studies have been published previously (Arwidi Å et al. Acta Radiol Oncol 18:273, 1979, Killander F et al. Eur J Cancer 43:2100, 2007, Killander F et al. The Breast 18:309, 2009). An efficient reduction of loco-regional recurrences but no improvement in survival was reported at 25 years of follow-up. Linkage to the following population based Swedish registries was obtained: 1. National Population Registry 2. National Cause of Death Registry, and 3. Swedish Hospital Discharge Registry. Per protocol treatment was administered to 1044 patients, which form the basis for the analyses. We have included both underlying and contributing causes of death due to heart, cerebrovascular and lung disease. Results: After 15 years a significantly increased cardiac mortality was observed in irradiated patients compared to patients given systemic treatment only, and this effect prevailed at 25 years of follow-up. However not until 15 years after radiotherapy significantly higher cardiovascular mortality was observed. When analysing cerebro-vascular mortality the same pattern was seen. Cumulative incidence of non-breast cancer mortality after postmastectomy radiation in pre-and For lung diseases no increase in mortality was discernible. An interesting observation was that in premenopausal patients cardiovascular and cerebrovascular mortality were less pronounced, and that the latency period was longer than for postmenopausal patients. Analyses of all hospital admissions during follow-up showed neither increased overall morbidity nor increased cardiovascular morbidity. Discussion: The significant cardiovascular side effects of radiation observed with the radiotherapy technique used in these studies underlines the importance of careful dose planning and reduction in the volumes of the heart and large vessels, that are exposed to radiation. Extended follow-up is necessary for detection of these late effects. The longer latency and lower cardiovascular mortality in premenopausal patients may reflect lower sensitivity for radiation of normal tissue compared to postmenopausal women. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-01.

Aims: To evaluate long-term effects of radiotherapy and tamoxifen after mastectomy on recurrence and survival in stage II breast cancer. Methods: A randomised phase III study with three treatment alternatives. (1) Radiotherapy 50 Gy/2S fractions to chest wall and regional lymph nodes (RT). (2) Radiotherapy and tamoxifen 30 mg/day for one year (RT + tam) and 3. Tamoxifen (tam). Results: 724 postmenopausal women were included between 1978 and 1985 and the trial was close to population based. Follow-up for survival was 23 years. Locoregional recurrences were reduced from 18.5% in the tam arm to 5.3% in the RT + tam arm. Overall mortality at 20 years was 71% in the RT arm, 68% in the RT + tam arm and 62% in the tam arm. The difference between RT + tam and tam was not significant except in the receptor positive subgroup in favour of non-irradiated patients (p = 0.047). The cumulative incidence of systemic disease at 20 years was lower in the RT + Tam arm than in the RT arm, 40% versus 50% (p = 0.047). Conclusion: Postmastectomy radiotherapy significantly reduced loco-regional recurrences, but overall survival was not improved. At 20 years, a lower mortality was recorded for non-irradiated patients treated with tam. (C) 2007 Published by Elsevier Ltd.

82 women who had had surgery for removal of breast cancer were randomised during the primary care period before initiation of any chemotherapy or radiotherapy into two groups: no drug treatment (n = 40) and 20 mg tamoxifen per day for 2 years (n = 42). Mononuclear leucocyte (MNL) fractions from blood samples were collected during the first 368 days of the study and ADP-ribosylation was quantified. Tamoxifen treatment resulted in a dose-duration increase in ADP-ribosylation. This was true even after adjustment for covariates such as age, smoking habits, oestrogen use, menstruation and tumour size. These data suggest that part of the antitumour effects of tamoxifen treatment in vivo relates to an enhanced immune cell responsiveness, as indicated by the increased MNL ADP-ribosylation.

PURPOSE: To study long term loco-regional and distant recurrence rate and survival after post-mastectomy radiotherapy in combination with oral cyclophosphamide in premenopausal women with stage II breast cancer. STUDY DESIGN: A three-armed randomized multicenter phase III trial comparing 1) Radiotherapy (RT) 2) RT+ oral cyclophosphamide for one year (RT+C) and 3) Oral cyclophosphamide only (C). Radiotherapy was administered, in 20 fractions, to 48Gy to the axilla and parasternal lymph nodes, 45Gy to infra- and supraclavicular fossae and 38Gy to the chest wall. Cyclophosphamide was prescribed as 12 courses of 130mg/m(2) od for14 days every 4 weeks. PATIENTS AND METHODS: 367 patients from 15 surgical departments in Southern Sweden, representing 80% of all eligible patients, were included in the trial between 1978-1983. Median age was 47 years, median tumour size was 25mm, and 33% of the patients were lymph node negative. Median follow-up time was 24 years. RESULTS: RT reduced the risk at twenty years for loco-regional recurrence in C-treated patients at twenty years with 75% (13.9% vs. 3.5%). The risk reduction was highly significant in both N0 and N+ patients. No reduction in systemic disease or mortality was observed. CONCLUSION: Post-mastectomy radiotherapy reduced loco-regional recurrences in this premenopausal population, but no effect was seen on mortality with 20 years follow-up. (Less)

BACKGROUND: A previous study has shown that pentoxifylline in combination with vitamin E can reverse radiation-induced fibrosis. The aim of the present study is to investigate if the same drugs could prevent radiation-induced side-effects in women with breast cancer. PATIENTS AND METHODS: A randomised, placebo-controlled, double-blind, parallel group trial was performed. Women with breast cancer were treated for 12months with 400mg pentoxifylline t.i.d. or placebo, in combination with 100mg vitamin E t.i.d., starting 1-3months after the completion of radiotherapy. The primary end-point was passive abduction of the shoulder, and the secondary end-point was difference in arm volumes. The trial is registered on the ISRCTN.org website, number ISRCTN39143623. RESULTS: 83 patients were included in the study; 42 in the pentoxifylline+vitamin E group and 41 in the placebo+vitamin E group. Both treatments were generally well tolerated. Seven patients were withdrawn from the treatment due to disease progression; four in the pentoxifylline group and three in the placebo group. At inclusion, patients had impaired passive abduction of the shoulder. During treatment, both the groups improved significantly. Median improvement from baseline was 3.7 degrees (p=0.0035) on pentoxifylline and was 9.4 degrees (p=0.0041) in the placebo group, but no difference between the groups was detected (p=0.20). Arm volumes increased over time in the placebo group (1.04%), but not on pentoxifylline (0.50%), and differed significantly between the groups (p=0.0172). CONCLUSIONS: The combination of pentoxifylline and vitamin E was safe and may be used for the prevention of some radiation-induced side-effects. (Less)

Abstract #5128 Purpose: To study long term loco-regional recurrence rate and survival after postmastectomy radiotherapy in combination with oral cyclophosphamide in premenopausal women with stage II breast cancer. Study design: A three-armed randomised, multicenter, phase III trial comparing 1) Radiotherapy (RT) 2) RT+ oral cyclophosphamide for one year (RT+C) and 3) cyclophosphamide only (C). Radiotherapy was administered with 48 Gy in 20 fractions to chest wall and locoregional lymph nodes (Arwidi Å, Acta Oncol Scand 18:273-281, 1979). Cyclophosphamide was prescribed as 12 courses of 130 mg/m2 od for14 days every 4 weeks. Patients and methods: 367 patients from 15 departments in Southern Sweden, representing 80% of all eligible patients, were included in the trial between 1978-1983; n=124 (RT), n=118 (RT+C), n=125 (C). Median age was 47 years, median tumour size was 25 mm, and 33 % of the patients were lymph node negative. Median follow up for survival was 24 years and 21 years for other events. Results: RT reduced the risk at twenty years for locoregional recurrence in C treated patients with 75 %, 13.9 vs 3.5 %. The risk reduction was highly significant in both N0 and N+ patients. RT did not decrease systemic disease or mortality, see table 1. Chemotherapy did not decrease mortality when added to radiotherapy, though difficult to evaluate because of lack of information on delivered doses in many cases. Conclusion: Postmastectomy radiotherapy reduces loco regional recurrences in this premenopausal population, but no effect was seen on mortality at 20 years. Possible explanations are 1) low number of loco regional recurrences and superior survival in comparison to other trials investigating postmastectomy radiotherapy, which might have modified the effect of RT on survival, 2) too low intensity of adjuvant, single agent chemotherapy, and 3) chance, since relatively small study with little power. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5128.