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Programmed death ligand-1 (PD-L1) immunostaining, which aids clinicians in decision-making on immunotherapy for non-small cell lung cancer (NSCLC) patients, is sometimes performed on cytological specimens. In this study, differences in cytology fixation and cell block (CB) processing between pathology laboratories were assessed, and the influence of these differences on interlaboratory variation in PD-L1 positivity was investigated. Questionnaires on cytology processing were sent to all Dutch laboratories. Information gathered from the responses was added to data on all Dutch NSCLC patients with a mention of PD-L1 testing in their cytopathology report from July 2017 to December 2018, retrieved from PALGA (the nationwide network and registry of histo- and cytopathology in the Netherlands). Case mix-adjusted PD-L1 positivity rates were determined for laboratories with known fixation and CB method. The influence of differences in cytology processing on interlaboratory variation in PD-L1 positivity was assessed by comparing positivity rates adjusted for differences in the variables fixative and CB method with positivity rates not adjusted for differences in these variables. Twenty-eight laboratories responded to the survey and reported 19 different combinations of fixation and CB method. Interlaboratory variation in PD-L1 positivity was assessed in 19 laboratories. Correcting for differences in the fixative and CB method resulted in a reduction (from eight (42.1%) to five (26.3%)) in the number of laboratories that differed significantly from the mean in PD-L1 positivity. Substantial variation in cytology fixation and CB processing methods was observed between Dutch pathology laboratories, which partially explains the existing considerable interlaboratory variation in PD-L1 positivity.

BACKGROUND Pregnancy-associated breast cancer (PABC), although most commonly defined as breast cancer diagnosed during pregnancy or within one year following delivery, knows a variety of definitions, likely related to the diversity of reported clinicopathological features and prognosis. More insight into the different breast cancer subgroups during pregnancy, the time after delivery and the postpartum period is therefore warranted. METHODS Patients with breast cancer diagnosed during pregnancy or within six months after delivery between January 1, 1988 and July 1, 2019, were included. Pregnant patients were subdivided according to gestational trimester, and postpartum patients according to lactational status. To investigate the influence of pregnancy and lactation on the histopathologic profile, these subgroups were compared to non-PABC patients matched for age at diagnosis, year at diagnosis, grade and ER status. Pearson Chi-square tests were used to compare clinicopathologic characteristics, while Kaplan-Meier/logrank/Cox regression methods were used to perform overall survival (OS) analysis. RESULTS Overall, 662 PABC patients were included, of which 73.6% were diagnosed during pregnancy. Median age at diagnosis was 34 years, with a median follow-up of 6.5 years. Overall, PABC patients as a group showed an advanced stage at diagnosis and an inferior OS at 5-years (75.4% vs. 83.2%, p = 0.000) compared to 1,392 non-PABC patients. In subgroup analysis, PABC patients within their first trimester showed a significantly lower tumor size and stage as compared to other trimesters. Patients diagnosed during the first trimester and postpartum non-lactating patients had a relatively good OS (81.3% and 77.9%, respectively) versus patients diagnosed during the second and third trimesters and during lactation (OS 60.0%, 64.9% and 65.6%, respectively, p = 0.003). In multivariate Cox regression, trimester of diagnosis, year of diagnosis, PR status, stage at diagnosis and surgery-or-not were significant contributors to OS. CONCLUSION In this large PABC cohort, uniquely specified by gestational trimester, an inferior outcome was found for patients diagnosed within the second and third gestational trimesters and during postpartum lactation, compared to first trimester and non-lactating postpartum patients. These findings indicate that PABC is clinically a heterogeneous group of breast cancer patients that should be redefined based on trimester of diagnosis and postpartum lactational status. Citation Format: Britt BM Suelmann, Carsten FJ Bakhuis, Carmen van Dooijeweert, Janneke Verloop, Ronald P Zweemer, Sabine C Linn, Elsken van der Wall, Paul J van Diest. Prognosis of pregnancy-associated breast cancer: Inferior outcome in patients diagnosed during second and third gestational trimesters and lactation [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 P3-12-06.

Objectives: Immunohistochemical expression of programmed death-ligand 1 (PD-L1) is used as a predictive biomarker for prescription of immunotherapy to non-small cell lung cancer (NSCLC) patients. Accurate assessment of PD-L1 expression is therefore crucial. In this study, the extent of interlaboratory variation in PD-L1 positivity in the Netherlands was assessed, using real-world clinical pathology data. Materials and Methods: Data on all NSCLC patients in the Netherlands with a mention of PD-L1 testing in their pathology report from July 2017 to December 2018 were extracted from PALGA, the nationwide network and registry of histo- and cytopathology in the Netherlands. PD-L1 positivity rates were determined for each laboratory that performed PD-L1 testing, with separate analyses for histological and cytological material. Two cutoffs (1% and 50%) were used to determine PD-L1 positivity. Differences between laboratories were assessed using funnel plots with 95% confidence limits around the overall mean. Results: 6,354 patients from 30 laboratories were included in the analysis of histology data. At the 1% cutoff, maximum interlaboratory variation was 39.1% (32.7%-71.8%) and ten laboratories (33.3%) differed significantly from the mean. Using the 50% cutoff, four laboratories (13.3%) differed significantly from the mean and maximum variation was 23.1% (17.2%-40.3%). In the analysis of cytology data, 1,868 patients from 23 laboratories were included. Eight laboratories (34.8%) differed significantly from the mean in the analyses of both cutoffs. Maximum variation was 41.2% (32.2%-73.4%) and 29.2% (14.7%-43.9%) using the 1% and 50% cutoffs, respectively. Conclusion: Considerable interlaboratory variation in PD-L1 positivity was observed. Variation was largest using the 1% cutoff. At the 50% cutoff, analysis of cytology data demonstrated a higher degree of variation than the analysis of histology data.

Background: Pregnancy associated breast cancer (PABC) comprises nearly 4% of all breast cancers. Compared to age-matched non-pregnant breast cancer patients, PABC is generally characterized by a particularly aggressive histopathologic profile. Whether these tumors arise before or during pregnancy, and whether they are stimulated by pregnancy-related hormones and/or epigenetic changes that by itself may affect subsequent hormone concentrations, remains to be elucidated. It is currently even unknown whether the histopathologic profile within PABC patients is affected by gestational age at diagnosis. In addition, some small studies observed a poorer outcome in lactating patients for patients with a postpartum PABC diagnosis. To fill this gap in knowledge, the present study assesses the influence of gestational age and lactation status at diagnosis on the histopathologic profile of PABC in a large population-based cohort.Methods:We identified 741 patients with PABC, between 1988 and 2019, in the nationwide Dutch Pathology Registry (PALGA). Histopathologic features (grade, ER-, PR-, and HER2-receptor status) were compared between pregnant- and postpartum PABC patients. Within pregnant PABC patients, histopathologic features were compared between the three gestational trimesters. For PABC patients with a postpartum diagnosis we compared histopathologic features of lactating versus non-lactating women.Results:Mean age at diagnosis was 34.2 years and the majority of breast cancers were diagnosed during pregnancy (74.2%); of which nearly half during the third trimester (47.3%). Histopathologic features did not differ between pregnant (n=550) and post-partum (n=191) PABC patients. Within pregnant patients, a significantly higher percentage of tumors were ER-receptor negative in the second (56.8%) and third trimester (57.3%), as compared to the first trimester (41.9%) (p=0.0015). A similar pattern was observed for PR; PR-negative receptor-status within first, second and third trimester: 48.0%, 57.7%, 56.5%, though these differences were not statistically significant (p=0.233). For histologic grade, we observed a higher proportion of grade III tumors with the second (87.4%) and third trimester (79.2%), as compared to the first trimester (73.7%) (p=0.055). For postpartum PABC patients no differences were observed for histologic grade between lactating (n=83) and non-lactating patients (n=94). However, tumors of lactating PABC patients were more often ER-negative (62.7% vs 48.9%, p=0.179), PR-negative (66.3% vs. 57.4%, p=0.258) and HER2-negative (74.7% vs. 61.7%, p=0.100). Conclusion:This unique, large population-based study of 741 PABC patients, demonstrates surprising histopathologic differences by gestational age at diagnosis for pregnant PABC-patients, and by lactation status for post-partum PABC-patients, which has not been reported before. Pregnant patients diagnosed at an advanced gestational age and postpartum PABC-patients who are lactating, seem to have a more aggressive histopathologic profile. This renders interesting clues for further studies, that will be conducted to unravel the molecular and genetic background and to investigate whether this has consequences on outcome. Citation Format: Britt BerendineMaria Suelmann, Carmen van Dooijeweert, Carsten Bakhuis, Elsken van der Wall, Sabine Linn, Paul van Diest. The histopathologic profile of pregnancy associated breast cancer by gestational age and lactation: Analysis of the nationwide Dutch Pathology Registry [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-14.

Histologic grade is a biomarker that is widely used to guide treatment of invasive breast cancer (IBC) and ductal carcinoma in situ of the breast (DCIS). Yet, currently, substantial grading variation between laboratories and pathologists exists in daily pathology practice. This study was conducted to evaluate whether an e-learning may be a feasible tool to decrease grading variation of (pre)malignant breast lesions. An e-learning module, representing the key-concepts of grading (pre)malignant breast lesions through gold standard digital images, was designed. Pathologists and residents could take part in either or both the separate modules on DCIS and IBC. Variation in grading of a digital set of lesions before and after the e-learning was compared in a fully-crossed study-design. Multiple outcome measures were assessed: inter-rater reliability (IRR) by Light’s kappa, the number of images graded unanimously, the number of images with both extreme scores (i.e., grade I and grade III), and the average number of discrepancies from expert-consensus. Participants were included as they completed both the pre- and post-e-learning set (DCIS-module: n = 36, IBC-module: n = 21). For DCIS, all outcome measures improved after e-learning, with the IRR improving from fair (kappa: 0.532) to good (kappa: 0.657). For IBC, all outcome measures for the subcategories tubular differentiation and mitosis improved, with >90% of participants agreeing on almost 90% of the images after the e-learning. In contrast, the IRR for the subcategory of nuclear pleomorphism remained fair (kappa: 0.523 vs. kappa: 0.571). This study shows that an e-learning module, in which pathologists and residents are trained in histologic grading of DCIS and IBC, is a feasible and promising tool to decrease grading variation of (pre)malignant breast lesions. This is highly relevant given the important role of histologic grading in clinical decision making of (pre)malignant breast lesions.

Background Histologic grade of ductal carcinoma in situ of the breast (DCIS) may become the single biomarker that decides whether patients will be treated. Yet, evidence shows that grading variation in daily practice is substantial. To facilitate quality improvement, feedback reports, in which laboratory-specific case-mix adjusted proportions per grade were benchmarked against other laboratories, were sent to the individual laboratories by March 1, 2018. One year later, the effect of these feedback reports on inter-laboratory variation was studied. Methods Synoptic pathology reports of all pure DCIS resection specimens between March 1, 2017 and March 1, 2019 were retrieved from PALGA (the nationwide Dutch pathology registry). Laboratory-specific proportions per grade were compared to the overall proportion in the year before and after feedback. The absolute deviation for all three grades at once, represented by the overall deviation score (ODS), was calculated as the sum of deviations from the grade-specific overall proportions. Case-mix adjusted, laboratory-specific odds ratios (ORs) for high- (grade III) versus low-grade (grade I-II) DCIS were obtained by multivariable logistic regression. Results Overall, 2954 DCIS reports from 31 laboratories were included. After feedback, the range between laboratories decreased by 22 and 6.5% for grades II and III, while an increase of 6.2% was observed for grade I. Both the mean ODS (27.2 to 24.1%) and maximum ODS (87.7 to 59.6%) decreased considerably. However, the range of case-mix adjusted ORs remained fairly stable and substantial (0.39 (95% CI: 0.18–0.86) to 3.69 (95% CI: 1.30–10.51)). Conclusion A promising decrease in grading variation was observed after laboratory-specific feedback for DCIS grades II-III, while this was not observed for DCIS grade I. Overall, grading variation remained substantial which needs to be addressed considering its clinical implications. Nationwide consensus on a classification, and training of (expert breast) pathologists, for example by e-learning, may help to further improve grading standardization.

AimsHistological grade is widely used to guide the management of invasive breast cancer (IBC). Yet, substantial interlaboratory and intralaboratory grading variations exist in daily pathology practice. To create awareness and to facilitate quality improvement, feedback reports, containing case-mix-adjusted laboratory-specific grades benchmarked against other laboratories, were sent to the individual laboratories by 1 March 2018. We studied the effect of these feedback reports on interlaboratory grading variation up till 1 year later.MethodsOverall, 17 102 synoptic pathology reports of IBC resection specimens from 33 laboratories, obtained between 1 March 2017 and 1 March 2019 were retrieved from the Dutch Pathology Registry (PALGA). An overall deviation score (ODS), representing the sum of deviations from the grade-specific overall proportions, was calculated to compare the absolute deviation for all grades at once. Case-mix correction was performed by two multivariable logistic regression analyses, providing laboratory-specific ORs for high-grade versus low-grade IBC.ResultsAfter feedback, the overall range between laboratories decreased by 3.8%, 6.4% and 6.6% for grades I, II and III, respectively. Though the mean ODS remained similar (13.8% vs 13.7%), the maximum ODS decreased from 34.1% to 29.4%. The range of laboratory-specific ORs decreased by 21.9% for grade III versus grades I–II.ConclusionsAn encouraging decrease in grading variation of IBC was observed after laboratory-specific feedback. Nevertheless, the overall grading variation remains substantial. In view of the important role of grading in patient management, it is adamant that not only feedback should be provided on a regular basis but also other interventions, such as additional training, are required.

TPS405 Background: Prostate cancer grading has been subject to variation, putting patients at risk for over- and under-treatment (Flach et al., 2022). As a response, development of artificial intelligence (AI) prostate cancer algorithms has been on the rise in the field of pathology. Despite promising results in retrospective studies, and several FDA-approved and CE-IVD certified algorithms on the market, prospective clinical implementation studies of AI are lacking. Moreover, uptake of digital pathology is currently insufficient due to high implementation costs (Ho et al., 2014). In this trial, we will explore the benefits of an AI-assisted pathology workflow in prostate cancer detection, while maintaining diagnostic safety standards. We will focus on reducing costly immunohistochemistry stains (IHC), which are currently used to aid in the diagnosis of prostate cancer. Methods: CONFIDENT-P is a SPIRIT-AI compliant single-centre, clinical trial, in a fully digital academic pathology laboratory. We will prospectively enroll 80 prostate cancer patients who undergo prostate needle biopsies. The pathology specimens will be pseudo-randomized to be assessed by a pathologist with- or without AI-assistance in a pragmatic (bi-)weekly sequential design, in a 1:1 allocation ratio. Patients are excluded when they are redirected for a second opinion to the UMC Utrecht. In the intervention group, pathologists will assess whole slide images (WSI) of the standard haematoxylin-eosin (HE)-stained sections assisted by the output of a CE-IVD approved prostate cancer detection and grading algorithm. In the control group, pathologists will assess HE WSI according to the current clinical workflow. If no tumour cells are identified or when the pathologist is in doubt, staining by immunohistochemistry (IHC) will be performed. Primary endpoint is the number of saved resources on IHC for detecting tumour cells, since this will clarify tangible cost savings that will help to build the business case for AI. We will compare the proportion of IHC-use in both arms, and calculate adjusted relative risks, using a log-binomial model. The sample size gives at least 80% power to detect a 30% difference in IHC usage, using a one-sided significance level of 5%. Enrolment is set to begin in November 2022. The ethics committee (MREC NedMec) waived the need of official ethical approval, as participants are not subjected to procedures and as they are not required to follow rules. Furthermore, they are not at risk of an inferior diagnosis. Trial registration is therefore applicable nor suitable.

AimSubstantial variation in Gleason grading (GG) of prostate cancer (PCa) exists between Dutch pathology laboratories. This study investigates its impact on treatment strategies.MethodsPathology reports of prostate needle biopsies and clinical data of patients with PCa diagnosed between 2017 and 2019 were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology and The Netherlands Cancer Registry. We investigated the impact of grading variation on treatment strategy for patients whose grade was decisive in treatment choice. First, we evaluated the effect of grading practice (low, average or high grading) on active treatment (AT) versus active surveillance in patients with prostate-specific antigen (PSA) ResultsWe included 30 509 patients. GG was decisive in treatment strategy for 11 925 patients (39%). AT was performed significantly less often in patients diagnosed by laboratories that graded lower than average (OR=0.77, 95% CI 0.68 to 0.88). Conversely, patients received AT significantly more often when diagnosed in high-grading laboratories versus average-grading laboratories (OR=1.21, 95% CI 1.03 to1.43). PLND was performed significantly less often in patients diagnosed by low-grading versus average-grading laboratories (OR=0.66, 95% CI 0.48 to 0.90).ConclusionOur study shows that the odds that a patient undergoes AT or PLND, depends on laboratories’ grading practices in a substantial number of patients. This likely influences patient prognosis and outcome, necessitating standardisation of GG to prevent suboptimal patient outcome.

Whether pregnancy-associated breast cancer (PABC) arise before or during pregnancy and whether this histopathology is affected by gestational age are currently unclear. The present study assesses the influence of gestational age and lactation on the histopathologic profile of PABC. We identified 744 patients with PABC (defined as breast cancer during pregnancy or 6 months following delivery). Histopathologic features were compared between pregnant and postpartum patients. We found that age at diagnosis was 34.2 years, and a majority of cancers were diagnosed during pregnancy (71.3%). Within pregnant patients, tumors were significantly more often estrogen receptor (ER)-negative in second and third trimesters (57.4%), as compared to first trimesters (41.9%) (P = 0.036). Similarly, a progesterone receptor (PR)-negative status was reported significantly less often within first trimesters (38.0%) compared to second and third trimesters (57.1%) (P = 0.032). For human EGF receptor 2 status, no significant differences were observed between gestational trimesters or lactating vs non-lactating patients. In postpartum patients, grade III tumors were found in over 80%, with high percentages of ER-negative tumors reaching 63% in those lactating vs 49% in non-lactating patients. This study demonstrates the varying histopathologic profile of PABC by gestational age and lactation status. Second- and third-trimester cancers display most typically the common ER/PR-negative phenotype, which is commonly reported in the literature. The increased ER-negative status and percentage grade III tumors in lactating vs non-lactating patients also suggest the presence of additional factors further diversifying histology. This indicates the need for clear definitions of PABC and the role of potential subgroups, which may provide a stepping stone for further in-depth research into PABC-carcinogenesis.

Simple Summary Gleason grading of prostate cancer is essential for treatment strategies and patient prognosis. Previous studies showed grading variation between pathologists when grading prostate cancer. Our study analyzed the presence and extent of grading variation between and within pathology laboratories in The Netherlands. In our nationwide retrospective study, we analyzed prostate needle biopsy reports of 35,258 patients in The Netherlands graded by 40 pathology laboratories. We found a considerable variation between and within pathology laboratories, as over half of the laboratories graded significantly different from the national mean. This likely affects treatment strategy and prognosis assessment of prostate cancer patients. Abstract Purpose: Our aim was to analyze grading variation between pathology laboratories and between pathologists within individual laboratories using nationwide real-life data. Methods: We retrieved synoptic (n = 13,397) and narrative (n = 29,377) needle biopsy reports from the Dutch Pathology Registry and prostate-specific antigen values from The Netherlands Cancer Registration for prostate cancer patients diagnosed between January 2017 and December 2019. We determined laboratory-specific proportions per histologic grade and unadjusted odds ratios (ORs) for International Society of Urological Pathologists Grades 1 vs. 2–5 for 40 laboratories due to treatment implications for higher grades. Pathologist-specific proportions were determined for 21 laboratories that consented to this part of analysis. The synoptic reports of 21 laboratories were used for analysis of case-mix correction for PSA, age, year of diagnosis, number of biopsies and positive cores. Results: A total of 38,321 reports of 35,258 patients were included. Grade 1 ranged between 19.7% and 44.3% per laboratory (national mean = 34.1%). Out of 40 laboratories, 22 (55%) reported a significantly deviant OR, ranging from 0.48 (95% confidence interval (CI) 0.39–0.59) to 1.54 (CI 1.22–1.93). Case-mix correction was performed for 10,294 reports, altering the status of 3/21 (14%) laboratories, but increasing the observed variation (20.8% vs. 17.7%). Within 15/21 (71%) of laboratories, significant inter-pathologist variation existed. Conclusion: Substantial variation in prostate cancer grading was observed between and within Dutch pathology laboratories. Case-mix correction did not explain the variation. Better standardization of prostate cancer grading is warranted to optimize and harmonize treatment.

INTRODUCTION AND OBJECTIVE:Gleason grading of prostate cancer (PCa) is essential for treatment strategy and prognosis of individual patients. Multiple studies showed inter-observer variation in gra...

The definition of PABC is inconsistently given as either breast cancer diagnosed exclusively during pregnancy, or combined with breast cancer diagnosed within six months to five years after delivery, and sometimes even longer. The longer away from the delivery date breast cancer is diagnosed, the less clear this association with pregnancy may become. Therefore, breast cancer diagnosed during pregnancy (BCdP) may not necessarily be the same disease entity as PABC. This review aims to provide an overview of BCdP receptor status, as this has not been assessed before. BCdP tumors were predominantly ER negative (56.6 %), PR negative (57.2 %) or both ER and PR negative (47.9 %). Moreover, HER2-overexpression was seen in 33.2 % of BCdP patients and 27.6 % had triple negative disease. This predominantly ER and PR negative profile with more often HER2 overexpression is aggressive and distinct from non-pregnant similar-aged patients, warranting future comparative research.

Accurate, consistent and reproducible grading by pathologists is of key‐importance for identification of individual patients with invasive breast cancer (IBC) that will or will not benefit from adjuvant systemic treatment. We studied the laboratory‐specific grading variation using nationwide real‐life data to create insight and awareness in grading variation. Synoptic pathology reports of all IBC resection‐specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch Pathology Registry (PALGA). Absolute differences in laboratory‐proportions of Grades I–III were compared to the national reference. Multivariable logistic regression provided laboratory‐specific odds ratios (ORs) for high‐ vs. low‐grade IBC. 33,792 IBC pathology reports of 33,043 patients from 39 laboratories were included, of which 28.1% were reported as Grade I (range between laboratories 16.3–43.3%), 47.6% as Grade II (38.4–57.8%), and 24.3% as Grade III (15.5–34.3%). Based on national guidelines, the indication for adjuvant chemotherapy was dependent on histologic grade in 29.9% of patients. After case‐mix correction, 20 laboratories (51.3%) showed a significantly deviant OR. Significant grading differences were also observed among pathologists within laboratories. In this cohort of 33,043 breast cancer patients, we observed substantial inter‐ and intra‐laboratory variation in histologic grading. It can be anticipated that this has influenced outcome including exposure to unnecessary toxicity, since choice of adjuvant chemotherapy was dependent on grade in nearly a third of patients. Better standardization and training seems warranted., What's new? Histologic grade serves a critical prognostic role in invasive breast cancer (IBC) and is used to guide therapeutic decisions. Evidence indicates, however, that IBC grading varies considerably. Here, grading variation in clinical practice was evaluated using real‐life data from laboratories in the nationwide Dutch Pathology Registry. Laboratories varied in IBC grade I, II, and III reporting. Among grading components, nuclear polymorphism showed the greatest difference between laboratories. Within laboratories, one‐third of pathologists deviated significantly from national proportions for IBC grade I. Despite deployment of uniform guidelines across laboratories, IBC histologic grading is not necessarily performed in a consistent manner.

Breast cancer treatment is largely guided by the results of tumor tissue analyses, i.e. evaluation of so called biomarkers, by pathologists. These biomarkers determine whether the tumor is sensitive to treatment with hormone therapy or treatment against the HER2-protein. Histologic grade represents the degree of aggressiveness and (co)determines whether additional treatment, for example with chemotherapy, is required. Given the importance of these biomarkers with regard to breast cancer treatment, we investigated whether there are differences in the results of biomarker assessment between pathology laboratories and between pathologists within individual laboratories. These analyses were performed with data from over 33.000 patients treated for breast cancer in the Netherlands between 2013 and 2016. Variation in biomarker assessment was limited, with exception of variation in grading, which was substantial, both between laboratories and between pathologists within the same laboratory. Realizing that grade is decisive for the indications for additional chemotherapy and hormone therapy in 35% and 30% of breast cancer patients, it seems likely that variation in grading lead to variation in treatment. This could potentially affect survival of breast cancer patients, which is still under investigation. To promote uniform grading, these data were reported back to the laboratories by means of feedback reports. An e-learning module, in which pathologists were trained in grading of breast cancer, was also developed. Both initiatives showed promising results. Additional initiatives, such as artificial intelligence, should be developed with priority to limit the variation in grading as much as possible.

Histologic grade is a biomarker that is widely used to guide treatment of invasive breast cancer (IBC) and ductal carcinoma in situ of the breast (DCIS). Yet, currently, substantial grading variation between laboratories and pathologists exists in daily pathology practice. This study was conducted to evaluate whether an e-learning may be a feasible tool to decrease grading variation of (pre)malignant breast lesions. An e-learning module, representing the key-concepts of grading (pre)malignant breast lesions through gold standard digital images, was designed. Pathologists and residents could take part in either or both the separate modules on DCIS and IBC. Variation in grading of a digital set of lesions before and after the e-learning was compared in a fully-crossed study-design. Multiple outcome measures were assessed: inter-rater reliability (IRR) by Light's kappa, the number of images graded unanimously, the number of images with both extreme scores (i.e., grade I and grade III), and the average number of discrepancies from expert-consensus. Participants were included as they completed both the pre- and post-e-learning set (DCIS-module: n = 36, IBC-module: n = 21). For DCIS, all outcome measures improved after e-learning, with the IRR improving from fair (kappa: 0.532) to good (kappa: 0.657). For IBC, all outcome measures for the subcategories tubular differentiation and mitosis improved, with90% of participants agreeing on almost 90% of the images after the e-learning. In contrast, the IRR for the subcategory of nuclear pleomorphism remained fair (kappa: 0.523 vs. kappa: 0.571). This study shows that an e-learning module, in which pathologists and residents are trained in histologic grading of DCIS and IBC, is a feasible and promising tool to decrease grading variation of (pre)malignant breast lesions. This is highly relevant given the important role of histologic grading in clinical decision making of (pre)malignant breast lesions.

Purpose: Patient management of invasive breast cancer (IBC) is to a large extent based on hormone- and HER2-receptor assessment. High-quality, reliable receptor assessment is of key importance as false results may lead to under- or overtreatment of patients. Surveillance of case-mix adjusted positivity rates has been suggested as a tool to identify laboratories with insufficient testing assays, as this covers the whole process of receptor assessment and enables laboratories to benchmark their positivity rates against other laboratories. We studied laboratory-specific variation in hormone- and HER2 positivity rates of 33,046 breast cancer patients using real-life nationwide data. Methods: All synoptic pathology reports of IBC resection-specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch pathology registry (PALGA). Absolute and case-mix adjusted receptor positivity rates were compared to the mean national proportion and presented in funnel plots in separate analyses for estrogen (ER), progesterone (PR) and HER2. Case-mix adjustment was performed by multivariable logistic regression. Results: 33,794 IBC lesions from 33,046 patients of 39 pathology laboratories were included. After case-mix adjustment, mean positivity rates were 87.2% for ER (range 80.4–94.3), 71.3% for PR (62.5–77.5%), and 9.9% for HER2 (5.5–12.7%). Overall, 14 (35.9%), 17 (43.6%) and 11 (28.2%) laboratories showed positivity rates outside the 95% confidence interval for ER, PR and HER2, respectively. Conclusion: This nationwide study shows that absolute variation in hormone- and HER2-receptor positivity rates between Dutch pathology laboratories is limited. Yet, the considerable number of outlying laboratories shows that there is still need for improvement. Continuous monitoring and benchmarking of positivity rates may help to realize this.

Purpose A considerable part of ductal carcinoma in situ (DCIS) lesions may never progress into invasive breast cancer. However, standard treatment consists of surgical excision. Trials aim to identify a subgroup of low-risk DCIS patients that can safely forgo surgical treatment based on histologic grade, which highlights the importance of accurate grading. Using real-life nationwide data, we aimed to create insight and awareness in grading variation of DCIS in daily clinical practice. Methods All synoptic pathology reports of pure DCIS resection specimens between 2013 and 2016 were retrieved from PALGA, the nationwide Dutch Pathology Registry. Absolute differences in proportions of grade I-III were visualized using funnel plots. Multivariable analysis was performed by logistic regression to correct for case-mix, providing odds ratios and 95% confidence intervals for high-grade (III) versus low-grade (I–II) DCIS. Results 4952 DCIS reports from 36 laboratories were included, of which 12.5% were reported as grade I (range 6.1–24.4%), 39.5% as grade II (18.2–57.6%), and 48.0% as grade III (30.2–72.7%). After correction for case-mix, 14 laboratories (38.9%) reported a significantly lower (n = 4) or higher (n = 10) proportion of high-grade DCIS than the reference laboratory. Adjusted ORs (95%CI) ranged from 0.52 (0.31–0.87) to 3.83 (1.42–10.39). Significant grading differences were also observed among pathologists within laboratories. Conclusion In this cohort of 4901 patients, we observed substantial inter- and intra-laboratory variation in DCIS grading, not explained by differences in case-mix. Therefore, there is an urgent need for nationwide standardization of grading practices, especially since the future management of DCIS may alter significantly depending on histologic grade. Electronic supplementary material The online version of this article (10.1007/s10549-018-05082-y) contains supplementary material, which is available to authorized users.

e12559 Background: Pregnancy associated breast cancer (PABC), defined as breast cancer diagnosed during or within one year after pregnancy, occurs approximately once in every 3,000 pregnancies and accounts for up to 6.9% of all breast cancers in women ≤ 45 years. Compared to age-matched non-PABC patients, PABC is generally characterized by a particularly aggressive histopathologic profile (more ER-, PR- and HER2 negative tumors and tumors of higher grade) with a higher mortality rate. Whether these cancers arise before or during pregnancy, and whether their genetic profile differs from non-PABC tumors, is currently unknown. This study assesses the genetic background of PABC by detection of specific DNA copy number alterations (CNA). Methods: We assembled 29 triple-negative PABC patients from the Dutch nationwide pathology database (PALGA). From their formalin-fixed and paraffin embedded (FFPE) tumor tissue blocks, DNA was extracted. Multiplex Ligation-Dependent probe Amplification (MLPA) analysis was performed for detection of CNAs in 20 oncogenes and 2 tumor suppressor genes using the P078-D2 kit (MRC Holland). Individual gene copy number loss (MLPA ratio < 0.7), gain (ratio 1.3-2.0) and amplification (ratio > 2.0) was determined and unsupervised hierarchical cluster analysis was performed to identify differences in copy number (CN) patterns between PABC patients. Chi square statistics were used to interrogate associations with clinicopathologic characteristics. Log-Rank test was used to compare Kaplan Meier survival curves between CN subgroups. Results: Triple negative PABC tumors showed frequent copy number loss on chromosome 17q ( CPD, MED1, TOP2A, MAPT, PPM1D) and 8p ( ZNF703 and ADAM9), as well as frequent copy number gain/amplification of MYC (8q) and CCND1 (11q). Cluster analysis identified 2 clusters of PABC patients based on their tumor copy number patterns: a CN-neutral cluster and a CN-high cluster, the latter demonstrating significantly lower chromosome 17 copy numbers than the former (for PPM1D, ERBB2, CPD, MED1, TOP2A, CDC6 and MAPT). Patients with CN-neutral tumors more often showed lymph node metastases (p = 0.028), were of significantly higher stage (p = 0.031), and demonstrated a worse overall survival (p = 0.036) compared with PABC patients harboring CN-high tumors. Conclusions: We demonstrate different tumor CN patterns within a small group of triple negative PABC-patients, associated with distinct aggressiveness. This will form the basis for further in-depth genetic profiling within a larger Dutch PABC cohort, rendering insight in the disease progression and contributing to the development of more targeted and personalized treatments.

Background: To date, histologic grade is widely used to guide therapeutic management of invasive breast cancer (IBC), as it remains one of the most well established prognostic biomarkers. In the Netherlands, with similar guidelines to the rest of Europe, grade even indicates the need for adjuvant chemotherapy in approximately one third of breast cancer patients. However, we previously showed that inter- and intra-laboratory variation in grading is substantial in daily pathology practice. To facilitate quality improvement of histologic grading, feedback reports were sent to all individual pathology laboratories. Reports included the case-mix adjusted laboratory proportions per grade, benchmarked against other laboratories and the nationwide average. Hence, pathologists were enabled to discuss and reflect upon their grading practices. We assessed the effect of these feedback reports on grading variation in daily pathology practice on a nationwide level. Methods: Synoptic pathology reports of all IBC resection specimens, obtained between March 1 2017 and March 1 2019 were retrieved from the Dutch nationwide pathology registry (PALGA). Feedback reports were sent on March 1 2018. Absolute differences in laboratory-proportions of grades I-III were compared to the overall nationwide proportion before (March 1, 2017 to March 1, 2018) and after the laboratories received their feedback reports (March 2, 2018 to March 1, 2019) from PALGA. To compare the absolute deviation for all grades at once, a SUM-score, representing the sum of deviations from the grade-specific nationwide proportions, was calculated. Case-mix correction was performed by multivariable logistic regression, providing laboratory-specific odds ratios (ORs) for high (grade II-III) versus low-grade (grade I) IBC. The multivariate ORs before and after the feedback reports were compared by Wilcoxon signed rank test. Results: We included 17,102 synoptic IBC reports from 33 laboratories of which 8,676 were reported before and 8,335 were reported after the feedback reports were sent. Nationwide proportions before and after the feedback reports were 30.5% and 32.0% for grade I, 49.5% and 49.2% for grade III, and 20.0% and 18.8% for grade III, respectively. After feedback, the total range between laboraratories decreased for all grades; from 17.5-45.5% to 17.3%-41.5% for grade I (range -3.8%), from 34.3-64.5% to 35.0-58.8% for grade II (range -6.4) and from 10.9%-37.1% to 9.9-29.5% for grade III (range -6.6%). The maximum SUM-score of 34.1% before the feedback reports decreased to 29.4% after feedback. However, SUM-scores per laboratory before and after the feedback reports did not significantly differ (Wilcoxon signed rank test, p=0.955). Furthermore, comparison of the multivariate ORs confirmed that changes were not significant (Wilcoxon signed rank test, p=0.640). Conclusion: After implementation of feedback reports, an encouraging decrease in nationwide grading variation was observed, reflected by the decrease of the absolute range between laboratories after the feedback reports for all grades (I-III) and the decrease of the maximum overall deviation (SUM-score). As feedback reports were sent by PALGA for the first time, this was not (yet) a closed quality loop. Hence, we do not know if and how laboratories implemented the feedback reports. Therefore, although feedback reports seem to decrease grading variation, the full potential of these reports is still unclear. However, overall grading variation remains substantial, which emphasizes that continuous monitoring and benchmarking is essential as it creates insight and awareness. Closing the quality loop and further training of pathologists, for example by e-learning, may help to further decrease grading variation and improve clinical decision making. Citation Format: Carmen van Dooijeweert, Paul J van Diest, Inge O Baas, Elsken van der Wall, Ivette AG Deckers. The effect of laboratory-specific feedback reports on grading variation of invasive breast cancer; results of a nationwide study in the Netherlands [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 P5-02-12.