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Background:Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups.Methods:The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 μg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG).Results:Overall, the optimal surveillance strategy was annual FIT (47 μg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 μg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 μg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG).Conclusions:Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy.Impact:Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.

Supplementary Figure from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

Supplementary Data from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

Supplementary Table from Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

Tamoxifen is widely used in the adjuvant treatment of estrogen receptor–positive (ER+) breast cancer and is an important drug for pre-menopausal women and post-menopausal patients who cannot tolerate aromatase inhibitors. Despite the clear clinical benefit in improving relapse-free and overall survival in these patients, an adverse effect of tamoxifen is a 2- to 7-fold increased risk of uterine cancer (UC) after 2-5 years of treatment. To date, the mechanism of tamoxifen-driven tumorigenesis is not well understood, and preventive approaches are lacking. Here, to molecularly characterize tamoxifen-associated uterine cancers (TA-UCs) and gain insights into their unique evolution, we performed whole-exome sequencing of 21 TA-UCs (discovery cohort) and droplet digital PCR (ddPCR) of an additional 40 TA-UCs (validation cohort) obtained from the ‘Tamoxifen Associated Malignancies: Aspects of Risk’ (TAMARISK) study. In addition, we used in vivo mouse models to: (i) further investigate tamoxifen-activated molecular pathways that may be involved in TA-UC tumorigenesis; and (ii) offer mechanistic insights. Overall, we discovered that TA-UCs were genomically similar to non–TA-UCs from The Cancer Genome Atlas (TCGA) project, with one profound exception: TA-UCs are characterized by a lower-than-expected frequency of mutations in two highly prevalent UC driver genes in the PI3K pathway: PIK3CA (14% [3/21] vs 48% [265/554] in non–TA-UC; P=0.003, Fisher’s exact test; Q=0.02, Benjamini-Hochberg FDR) and PIK3R1 (0%, [0/21] vs 31% [174/554]; P=0.001; Q=0.01). We used ddPCR in the independent TA-UC validation cohort and confirmed the low frequency of mutations in PIK3CA (7.5% [3/40] vs 21% [144/685] in control UCs from the Dana-Farber contribution to the AACR GENIE project; P=0.04). We next performed mouse in vivo studies and demonstrated that tamoxifen activated the PI3K pathway and increased cell proliferation in normal mouse uterine tissue through paracrine and autocrine effects, both of which were abrogated by the PI3K inhibitor alpelisib. Taken together, we describe a distinct and novel pathway of carcinogenesis in which tamoxifen acts as a driver event in the uterus and promotes tumor development in a mutation-independent manner. Indeed, tamoxifen may increase the risk of UC by activating the PI3K pathway, which can substitute for the early acquisition of oncogenic PIK3CA or PIK3R1 mutations observed in non–TA-UC tumors. Furthermore, the ability of a PI3K inhibitor to reduce cell proliferation in our mouse model raises the possibility that downregulating the PI3K pathway may prevent or significantly reduce TA-UC development, offering a potential future therapeutic and prevention strategy for specific high-risk patients undergoing tamoxifen therapy. Citation Format: Kirsten Kubler, Agostina Nardone, Shankara Anand, Daniel Gorvich, Marjolein Droog, Francisco Hermida-Prado, Tara Akshi, Avery S Feit, Gabriella Cohen, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, William J Gibson, Cloud P Paweletz, Eliezer M Van Allen, Flora E van Leeuwen, Petra Nederlof, Harry Hollema, Quang-Dé Nguyen, Marian JE Mourits, Ignaty Leshchiner, Chip Stewart, Ursula A Matulonis, Wilbert Zwart, Yosef E Maruvka, Gad Getz, Rinath Jeselsohn. Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-09.

Purpose: Ductal carcinoma in situ (DCIS) is treated to prevent progression to invasive breast cancer. Yet, most lesions will never progress, implying that overtreatment exists. Therefore, we aimed to identify factors distinguishing harmless from potentially hazardous DCIS using a nested case–control study.Experimental Design: We conducted a case–control study nested in a population-based cohort of patients with DCIS treated with breast-conserving surgery (BCS) alone (N = 2,658) between 1989 and 2005. We compared clinical, pathologic, and IHC DCIS characteristics of 200 women who subsequently developed ipsilateral invasive breast cancer (iIBC; cases) and 474 women who did not (controls), in a matched setting. Median follow-up time was 12.0 years (interquartile range, 9.0–15.3). Conditional logistic regression models were used to assess associations of various factors with subsequent iIBC risk after primary DCIS.Results: High COX-2 protein expression showed the strongest association with subsequent iIBC [OR = 2.97; 95% confidence interval (95% CI), 1.72–5.10]. In addition, HER2 overexpression (OR = 1.56; 95% CI, 1.05–2.31) and presence of periductal fibrosis (OR = 1.44; 95% CI, 1.01–2.06) were associated with subsequent iIBC risk. Patients with HER2+/COX-2high DCIS had a 4-fold higher risk of subsequent iIBC (vs. HER2−/COX-2low DCIS), and an estimated 22.8% cumulative risk of developing subsequent iIBC at 15 years.Conclusions: With this unbiased study design and representative group of patients with DCIS treated by BCS alone, COX-2, HER2, and periductal fibrosis were revealed as promising markers predicting progression of DCIS into iIBC. Validation will be done in independent datasets. Ultimately, this will aid individual risk stratification of women with primary DCIS. Clin Cancer Res; 24(15); 3593–601. ©2018 AACR.

Class 4/5 mutations and Tumor Mutational Burden stratified by loss of heterozygosity status.

Examples of morphological characteristics associated with gBRCA/LOHpos ECs.

Germline BRCA1/2 Mutations and Variant Allele Frequencies detected in the FFPE-isolated tumor DNA

Purpose:Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship.Experimental Design:Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined “gBRCA-associated,” those without LOH (gBRCA/LOHneg) were defined “sporadic.”Results:LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%).Conclusions:We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers.

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CD8-positive T-cell infiltrate stratified by loss of heterozygosity status.

Supplementary Tables

Clinicopathologic characteristics of the complete cohort

Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3).Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.

Overall survival of women with gBRCA/LOHpos ECs (n=24) and gBRCA/LOHneg ECs (n=16).

Supplementary Materials and Methods

Supplementary Table 1. Clinical characteristics of BRCA1/2 carriers including index cases in the Northern Netherlands (study population) and in the rest of the Netherlands (reference population). Supplementary Table 2. Overview of number of carriers (excluding index cases) at risk at each age-decade and number of breast cancer event for each age-decade. Supplementary Table 3. Cumulative incidence of breast cancer in BRCA1/2 carriers, excluding index cases, in the study population (Northern Netherlands) and reference population (rest of the Netherlands). Estimation of risks weighted to an equal contribution from the different birth cohorts in each population. Supplementary Table 4. Relative risks (hazard ratios (95% confidence interval)) of breast cancer for mutation spectrum, excluding index cases. Supplementary Table 5. Regional differences in the breast cancer risk of BRCA1/2 carriers including index cases (adjusted for birth year) in the Netherlands: the study population (Northern Netherlands) compared to the reference population (the rest of the Netherlands.)

Supplementary Material and Methods

Background: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk.Methods: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum.Results: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11–14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 BRCA2 ≥60 years by −3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97–1.09).Conclusions: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers.Impact: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60. Cancer Epidemiol Biomarkers Prev; 23(11); 2482–91. ©2014 AACR.

Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773–84. ©2016 AACR.

Primer sequences corresponding with supplemental figure S5.

Kaplan-Meier survival plot of endometrial cancer patients who were not treated with tamoxifen for their breast cancer, categorized as ERalpha+/FOXA1+, ERalpha+/FOXA1-, ERalpha-/FOXA1+ or ERalpha-/FOXA1-.

Box plot, depicting interval time (years) between breast cancer diagnosis and endometrial cancer diagnosis and endometrial cancer diagnosis for patients who did not receive tamoxifen.

RT-PCR analysis of 20 transcription factors in four tamoxifen-associated endometrial tumors and Ishikawa cells. Corresponding primers can be found in supplementary table S6.

Scatter plot showing the relationship between ERalpha (X-axis) and FOXA1 (Y-axis) staining

supplementary methods

ChIP-seq read count and mapped reads of endometrial tumors.

2D graph, showing normalized read count of the shared binding sites for ERalpha and FOXA1 (blue), ERalpha only (red) and FOXA1 only (green) in ChIP-seq datasets of all indicated transcriptional regulators in the endometrial cancer cell line Ishikawa (ENCODE, see Supplementary table S4).

ChIP-QPCR validation of ChIP-seq peaks found in endometrial cancer specimens.

Clinicopathological parameters of patient samples in the TAMARISK-study. MC-UC = interval between breast cancer and endometrial cancer.

Accession numbers of Ishikawa RNA-seq and ChIP-seq datasets generated by the ENCODE consortium and publicly available ERalpha ChIP-seq data from breast tumors.

Biological replicates of ChIP-seq analyses for ERalpha (A), RNA Polymerase II (B), H3K27Ac (C) and FOXA1 (D).

Validation of two FOXA1 antibodies that were used for either ChIP or immunohistochemistry.

Clinocopathological parameters of breast cancers used for ChIP-seq

Ingenuity Pathway Analysis on genes with ERalpha, FOXA1 or both in the gene body or within 20 kb upstream from the Transcriptional Start Site.

Primer sequences corresponding with supplemental figure S2, to validate ChIP-seq on qPCR.

legends to supplementary tables and figures

Patient characteristics of endometrioid adenocarcinomas used for ChIP-seq.

Purpose: Ductal carcinoma in situ (DCIS) is treated to prevent progression to invasive breast cancer. Yet, most lesions will never progress, implying that overtreatment exists. Therefore, we aimed to identify factors distinguishing harmless from potentially hazardous DCIS using a nested case–control study. Experimental Design: We conducted a case–control study nested in a population-based cohort of patients with DCIS treated with breast-conserving surgery (BCS) alone (N = 2,658) between 1989 and 2005. We compared clinical, pathologic, and IHC DCIS characteristics of 200 women who subsequently developed ipsilateral invasive breast cancer (iIBC; cases) and 474 women who did not (controls), in a matched setting. Median follow-up time was 12.0 years (interquartile range, 9.0–15.3). Conditional logistic regression models were used to assess associations of various factors with subsequent iIBC risk after primary DCIS. Results: High COX-2 protein expression showed the strongest association with subsequent iIBC [OR = 2.97; 95% confidence interval (95% CI), 1.72–5.10]. In addition, HER2 overexpression (OR = 1.56; 95% CI, 1.05–2.31) and presence of periductal fibrosis (OR = 1.44; 95% CI, 1.01–2.06) were associated with subsequent iIBC risk. Patients with HER2+/COX-2high DCIS had a 4-fold higher risk of subsequent iIBC (vs. HER2−/COX-2low DCIS), and an estimated 22.8% cumulative risk of developing subsequent iIBC at 15 years. Conclusions: With this unbiased study design and representative group of patients with DCIS treated by BCS alone, COX-2, HER2, and periductal fibrosis were revealed as promising markers predicting progression of DCIS into iIBC. Validation will be done in independent datasets. Ultimately, this will aid individual risk stratification of women with primary DCIS. Clin Cancer Res; 24(15); 3593–601. ©2018 AACR.

Background: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a small number of studies. Methods: We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox proportional hazards framework. Results: There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had ever used OC were at a significantly reduced risk of developing ovarian cancer (hazard ratio, 0.52; 95% confidence intervals, 0.37-0.73; P = 0.0002) and increasing duration of OC use was associated with a reduced ovarian cancer risk (P trend = 0.0004). The protective effect of OC use for BRCA1 mutation carriers seemed to be greater among more recent users. Tubal ligation was associated with a reduced risk of ovarian cancer for BRCA1 carriers (hazard ratio, 0.42; 95% confidence intervals, 0.22-0.80; P = 0.008). The number of ovarian cancer cases in BRCA2 mutation carriers was too small to draw definitive conclusions. Conclusions: The results provide further confirmation that OC use, number of full-term pregnancies, and tubal ligation are associated with ovarian cancer risk in BRCA1 carriers to a similar relative extent as in the general population. (Cancer Epidemiol Biomarkers Prev 2009;18(2):601–10)

Objective: To assess the epidemiologic evidence for the association between physical activity and endometrial cancer risk, taking into account the methodologic quality of each study. Design: Systematic review, best evidence synthesis. Data Sources: Studies were identified through a systematic review of literature available on PubMed through December 2006. Review Methods: We included cohort and case-control studies that assessed total and/or leisure time and/or occupational activities in relation to the incidence of endometrial cancer. The methodologic quality of the studies was assessed with a comprehensive scoring system. Results: The included cohort (n = 7) and case-control (n = 13) studies consistently show that physical activity is associated with a decreased risk of endometrial cancer. The best evidence synthesis showed that the majority (80%) of 10 high-quality studies found risk reductions of >20%. Pooling of seven high-quality cohort studies that measured total, leisure time, or occupational activity showed a significantly decreased risk of endometrial cancer (summary estimate: OR, 0.77; 95% CI, 0.70-0.85) for the most active women. Case control studies with relatively unfavorable quality scores reported divergent risk estimates, between 2-fold decreased and 2-fold increased risk. Effect modification by body mass index or menopausal status was not consistently observed. Evidence for an effect of physical activity during childhood or adolescence was limited. Conclusions: Physical activity seems to be associated with a reduction in the risk of endometrial cancer, which is independent of body weight. Further studies, preferably prospective cohort studies, are needed to determine the magnitude of the risk reduction and to assess which aspects of physical activity contribute most strongly to the reduced risk and in which period of life physical activity is most effective. (Cancer Epidemiol Biomarkers Prev 2007;16(4):639–48)

INTRODUCTION. The wide spread adoption of population-based breast cancer screening has led to a substantial increase in diagnosis of ductal carcinoma in situ (DCIS). When detected, almost all DCIS is treated to prevent progression to invasive disease, even though the majority of DCIS will never progress. Yet, we are unable to discriminate harmless from potentially hazardous DCIS. Hence, there is an urgent need to find characteristics of DCIS and biomarkers that predict subsequent invasive tumor development. In this study, we compared primary DCIS lesions with their subsequent ipsilateral invasive breast cancer (iIBC), to explore how the initial DCIS lesion and its subsequent iIBC are related. PATIENTS AND METHODS. We used a population-based, nation-wide cohort consisting of 2,654 women who were treated for primary DCIS by breast conserving surgery (BCS) only. Within a median follow-up time of 10.7 years, 316 women developed a subsequent iIBC (12%). FFPE tissue blocks of both DCIS and subsequent iIBC could be collected for 158 of these 316 women. We assessed histology characteristics, tumor location, estrogen and progesterone receptor status, p16 expression, and HER2 and p53 overexpression. Additionally, DNA and RNA were simultaneously isolated from 100 DCIS and 100 matched subsequent iIBC specimens for extensive molecular profiling. RESULTS. More than 95% of the invasive recurrences were located at or near the site of the primary DCIS. Concordant histological grade was found in 94% of the matched pairs and identical immunohistochemical (IHC) marker expression in 58%. Of the 44 patients with HER2 positive DCIS, 36% developed HER2 negative iIBC. Furthermore, this change in HER2 status was also a main cause of a change in surrogate intrinsic subtype (based on ER, PR, HER2) between DCIS and iIBC, which was observed in 16% of the patients. These dissimilarities were not found when we compared invasive disease with synchronous DCIS (present in 83 of 158 patients). Molecular analyses is still ongoing. CONCLUSION. This is the first time that an unbiased comparison could be made between primary DCIS and its subsequent iIBC within such a large patient group, integrating clinical, histological and IHC data. Our results suggest that the majority of invasive breast cancers in our cohort reflect outgrowth of residual disease based on tumor location and histological grade. DCIS and iIBC are very similar when comparing histological grade, but frequently show differences on the IHC level. Remarkably, the dissimilarities in HER2 status and surrogate intrinsic subtype as seen in primary DCIS vs. iIBC are missing when comparing IBC with synchronous DCIS. As a next step, we will analyse the lesions on the molecular level, to verify these findings and to look for molecular characteristics of DCIS that could be associated with progression to invasive disease. Citation Format: Lindy L. Visser, Lotte L. Elshof, Koen van de Vijver, Emma J. Groen, Mathilde Almekinders, Marjanka K. Schmidt, Flora van Leeuwen, Emiel J. Rutgers, Michael Schaapveld, Esther H. Lips, Jelle Wesseling. Risk of ipsilateral invasive breast cancer after DCIS: a comparison of primary DCIS and subsequent invasive disease by morphological and immunohistochemical analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4738. doi:10.1158/1538-7445.AM2017-4738

The biological background and different pathological aspects of BRCA1-associated tumors support the hypothesis that patients carrying a BRCA1 and/or BRCA2 mutation might have a worse breast cancer prognosis compared to non-carriers. However, studies showed inconsistent results, possibly due to differences in study design, study size, study populations and methodological quality. We recently performed a systematic review taking into account the quality of all relevant studies published so far on BRCA1/2 mutation carriership and survival (n=63). Using a best-evidence synthesis, we found that there is only moderate evidence for a worse unadjusted recurrence-free survival for BRCA1 mutation carriers compared to non-carriers (pooled absolute survival difference of 10%) (to be submitted). The aim of the current study was to evaluate breast cancer outcome in a multicenter cohort of breast cancer patients with long-term follow-up, unselected for family history. We included invasive pathologically-confirmed breast cancers, diagnosed before Among 5518 breast cancer patients with a BRCA1/2 result we found 3.6% BRCA1 and 1.2% BRCA2 mutation carriers. The proportions of ER-positive breast cancers in non-BRCA, BRCA1 and BRCA2 mutation carriers were 86%, 29% and 81% respectively. Mean follow-up of the cohort was 11.3 years. Overall survival was worse for BRCA1 mutation carriers compared to non-carriers (HR-unadjusted 1.4 (95%CI: 1.1-1.7), p=0.003; HR-adjusted 1.2 (1-1.6), p=0.07); recurrence-free survival was also worse for BRCA1 mutation carriers (HR-adjusted 1.5 (1.1-1.9), p=0.004). We did not find evidence for a different survival of BRCA2 mutation carriers, except for a suggestion of a worse overall survival. These results are preliminary and further analyses including stratifications by tumor subtype and treatment will be presented at the AACR meeting. In one of the largest, unbiased, BRCA1/2 genotyped breast cancer cohort study, we found evidence for a significant worse overall and recurrence-free survival adjusted for clinico-pathological factors of BRCA1 mutation carriers. Citation Format: Marjanka MK Schmidt, Alexandra J. van den Broek, Rob AEM Tollenaar, Flora E. van Leeuwen, Laura J. Van ‘t Veer, on behalf of collaborators of 10 centers in the Netherlands. Breast cancer survival of BRCA1/2 carriers compared to non-BRCA1/2 carriers in a large breast cancer cohort. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1338. doi:10.1158/1538-7445.AM2013-1338