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Background: The 2020 ASCO-CAP guidelines (Allison KH, JCO 2020; 38: 1346–66) recommended estrogen receptor (ER) Low Positive as new reporting category for breast cancers with 1-10% of cells staining ER positive to acknowledge their distinct clinical behaviour compared to breast cancers with >10% to 100% of tumor nuclei positive for ER. We evaluated the prognostic impact of low ER positivity with both 10% and 33% as cut-off. Patients and methods: A retrospective study was performed of consecutively treated patients in UZ Leuven between 2000-2017 with ER-positive/HER2-negative early, primary, unilateral and unifocal grade 2-3 invasive breast cancers. Patients treated with neo-adjuvant therapy were excluded. ER-positivity was defined as >1% ER-staining on immunohistochemistry (IHC). Patients were allocated to ER-low or ER-high groups for both the 10% and 33% thresholds according to their ER-status on IHC as derived from the Allred PS or from the H-score. Descriptive analyses and Cox regression analyses were performed for both thresholds (≤ 10% vs. ≤ 33%) with α=0.05. Primary endpoints were overall survival (OS) and invasive disease-free survival (iDFS). Secondary endpoints were time to local (TTLR), locoregional (TTLRR) and distant metastatic relapse (TTM). Results: This study included 3629 patients (median age: 60.0 years; median follow-up: 12.3 years), with their tumors classified as low (39) versus high (3590) with 10% threshold and as low (92) versus high (3537) with 33% threshold. According to both cut-offs, grade 3 and PR negativity was more frequent in ER Low Positive breast cancer. These patients also received significantly more adjuvant chemotherapy and less adjuvant endocrine therapy. When looking at iDFS, OS, TTLR and TTLRR, both cut-offs generated groups with similar outcome. However, we observed a significant increased risk for distant metastatic relapse in ER Low Positive disease using the cut-off of 33% (univariate HR 2.0, 95%CI 1.3-3.2; p=0.009), which was not present for the cut-off of 10% (univariate HR 0.5, 95%CI 0.1-1.8; p=0.2). Nevertheless, when correcting this effect for age, grade, PR, tumor size, nodal status, adjuvant chemotherapy and endocrine therapy in multivariate analysis, ER Low Positive according to the cut-off of 33% did not remain significant to predict risk for metastatic relapse (HR 1.3, 95%CI: 0.8-2.3; p=0.3). Conclusion: In our series, patients with tumors expressing low ER, defined as 1-33% had a significantly higher univariate risk for metastatic relapse. ER Low Positive tumors are more frequently grade 3, which greatly determines the prognosis. ER Low Positivity did not remain independently significant after multivariate analysis. However, patients with tumors expressing low ER only constituted small fractions of the investigated population. Citation Format: Bernard Roobroeck, Adriaan Vanderstichele, Giuseppe Floris, Christine Desmedt, Kevin Punie, Sileny Han, Ann Smeets, Hilde Janssen, Adinda Baten, Caroline Weltens, Ines Nevelsteen, Thaïs Baert, Hans Wildiers, Patrick Neven. Challenging the current 1-10% cut-off for defining Estrogen Receptor Low Positive grade 2-3 Estrogen Receptor positive, Human Epidermal growth factor Receptor 2 negative early breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-20.

Background The Regan Composite Risk Score (RCRS) is a web-based prognostic and predictive calculator to guide the use of adjuvant exemestane plus ovarian function suppression (AI + OFS) versus tamoxifen plus ovarian function suppression (TAM + OFS) or tamoxifen alone (TAM) for premenopausal women with hormone receptor-positive HER2-negative early breast cancer (HR+/HER2- EBC). We compared our adjuvant endocrine therapy policy based on the tumor board with the treatment guided by the RCRS during 2 time periods, one before and one after the acquaintance of the Tamoxifen and Exemestane Trial (TEXT) and Suppression and Ovarian Function Trial (SOFT) data. This allowed us to see a possible evolution in therapy policy. Methods A retrospective cohort study of 563 premenopausal patients with HR+/HER2- and HER2+ EBC diagnosed at the University Hospital of Leuven during 2 periods, 2010-2012 (cohort 1) and 2015-2017 (cohort 2), was conducted. For each patient with HER2- EBC, the RCRS was calculated by entering the requested characteristics in the online available tool. The primary outcome was to investigate how frequent our therapy differed from the therapy guided by the RCRS based on the estimated 8-yr distant relapse free interval (DRFI) with an arbitrary cut-off set at 3 %. If the received therapy was ≥ 3 % less efficient in 8-year DRFI compared to the optimal therapy according to RCRS, the patient was considered undertreated. If the received therapy differed by less than 3 % in 8-year DRFI compared to the optimal therapy according to RCRS and yet the most intensive therapy (AI + OFS > TAM + OFS > TAM) was administered, the patient was considered overtreated. In the other cases, the patient was considered to have been treated concordant with the RCRS. Secondarily, nonadherence of the HER2- and HER2+ patients towards the endocrine treatments leading to therapy switch because of intolerance was recorded at 6, 12, 24 and 36 months. Analyses were performed using SAS software and the comparison of both cohorts was performed by the chi-squared test for categorical variables. Results According to the RCRS, 43.2 % (89/206) of the HER2-negative patients of cohort 1 were undertreated compared to 22.1 % (43/194) in cohort 2 (chi- squared test, p-value < 0.001). The number of overtreated patients also differed significantly between the two cohorts (chi-squared test, p-value = 0.003) with 2.9 % (6/206) in the first cohort and 10.3 % (20/194) in the second cohort. Finally, the number of patients treated concordant with the guidance derived from the RCRS was 53.9 % (111/206) in cohort 1 and 67.5 % (131/194) in cohort 2 (chi-squared test, p-value = 0.005). Treatment intolerance and switch was observed in 34.8 %, 16.7 % and 12.4 % of the patients receiving AI + OFS, TAM + OFS or TAM as initial therapy respectively; this was numerically higher for all treatments in cohort 2 vs cohort 1, although the observed difference was only significant for TAM. Conclusion In our center, a recent cohort of premenopausal women was more likely to be treated with the adjuvant endocrine treatment concordant with the guidance derived from the RCRS when using an arbitrary cut-off of 3 % to define a relevant improvement in outcome. Citation Format: Charlotte Berteloot, Patrick Neven, Maja Vangoitsenhoven, Annouschka Laenen, Hans Wildiers, Kevin Punie, Ann Smeets, Ines Nevelsteen, Sileny Han, Thaïs Baert, Hilde Janssen, Eva Oldenburger, Adinda Baten, Patrick Berteloot, Rani Vanhoudt, Anne Deblander, Chantal Remmeriev, Christine Desmedt. Real world adjuvant endocrine treatment in premenopausal breast cancer patients compared with the proposed algorithm using the Regan Composite Risk Score [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-04.

Background and objective: Invasive micropapillary carcinoma (IMPC) of the breast is a special variant of breast carcinoma with a unique morphology. Data about long-term outcome are conflicting and reports on stromal tumor infiltrating lymphocytes (sTILs) and their correlation with prognosis are scarce. In this retrospective cohort study we aimed to describe clinical and pathological features of IMPC, including sTILs assessment and immunohistochemistry studies, and their correlation with long-term outcome. Materials and methods: Patients with stage I-III IMPC (pure and mixed forms) who underwent upfront surgery at our institution between 2000 and 2016 were included. All patients signed informed consent. Standard clinico-pathological features and follow-up data to calculate distant relapse-free interval and breast cancer-specific survival were obtained from clinical records. Pathologic review of representative H&E-slides of the resection specimens included evaluation of sTILs and assessment of the micropapillary component. Surrogate molecular subtypes were based on receptor-status and histological grade. Using tissue microarrays we assessed by immunohistochemistry the pattern of staining of P53, and scored semi-qualitatively the expression of Bcl2, PAX8 and WT1. The association between predictors and outcome is analyzed using the Fine and Gray model, accounting for other-cause death as competing event. All tests are two-sided, assuming a 5% significance level. The sample size did not allow multivariate analysis. Results: We included 111 patients (median age 61,5 years; range 33-88). Luminal surrogate subtypes were most prevalent with 51 luminal A-like, 41 luminal B-like, 12 luminal HER2+, 5 HER2+ and 2 triple negative IMPC. 89% of patients had a T1 or T2 tumor and 50% of IMPC were poorly differentiated. Lymph node involvement was present in 59% and lymphovascular invasion in 44% of cases. Adjuvant chemotherapy, radiotherapy and endocrine therapy was administered in 47%, 87% and 90% of patients, respectively. Of all cases 59% were pure IMPC. Standard clinico-pathological features were comparable between pure and non-pure IMPC. sTILs were classified as low (50%) in 78%, 14% and 8% of specimens respectively. Comparison between surrogate subtypes showed higher sTILs (p=0.025) and a higher likelihood of aberrant P53 expression (p Citation Format: Kevin Punie, Frederik Deman, Annouschka Laenen, Timothy Faes, Hans Wildiers, Ann Smeets, Ines Nevelsteen, Chantal Van Ongeval, Adinda Baten, Melissa Christiaens, Eva Oldenburger, Hilde Janssen, Caroline Weltens, Tatjana Geukens, Nynke Willers, Jan Ardui, Hava Izci, Laurence Slembrouck, Patrick Neven, Christine Desmedt, Giuseppe Floris. Clinical and pathological features of invasive micropapillary carcinoma of the breast and correlation with prognosis [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 P3-08-31.

Simple Summary Breast cancer is the most common cancer in females worldwide. To date, many gene-environment interaction (GxE) studies have been conducted to better understand how genetic factors combine with environmental factors to influence risk. However, previous studies have not found or found only a few interactions by using SNPs which were discovered from genome-wide association studies and have been conducted, for the most part, within European populations. In this study, we focused on estrogen-related lifestyle factors that have been identified for breast cancer, including several well-established reproductive factors that are mediated by hormonal mechanisms. We aimed to examine whether there are any gene and environmental factor interactions related to estrogen exposure or metabolism using a candidate approach in Korean women. We found two interactions in this study, although they were not replicated in the independent large consortium data. These findings suggest specificity in Koreans for breast cancer risk. In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 x 10(-3)). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 x 10(-4)). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

PURPOSE: We studied the long-term outcomes of invasive micropapillary carcinoma (IMPCs) of the breast in relation to stromal tumor infiltrating lymphocytes (sTILs), prognostic biomarkers and clinicopathological features. METHODS: Stage I-III IMPCs treated with upfront surgery at our institution (January 2000 and December 2016) were included. Central pathology review was performed and sTILs (including zonal distribution and hot spot analysis) and tumor-associated plasma cells (TAPC) were evaluated. Expression of P53, BCL2, FOXP3, and WT1, which are variably linked to breast cancer prognosis, was measured by immunohistochemistry using tissue microarrays. Time-to-event endpoints were distant recurrence free interval (DRFI) and breast cancer-specific survival (BCSS). RESULTS: We included 111 patients of whom 59% were pure IMPCs. Standard clinicopathological features were comparable between pure and non-pure IMPCs. Overall, the mean sTILs level was 20% with higher proportion of sTILs present at the invasive front. There were no significant differences between pure- and non-pure IMPCs in sTILs levels, nor in the spatial distribution of the hot spot regions or in the distribution of TAPC. Higher sTILs correlated with worse DRFI (HR = 1.55; p = 0.0172) and BCSS (HR = 2.10; p