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Introduction Neoadjuvant systemic therapy (NST) is increasingly applied in breast cancer to increase breast-conserving surgery (BCS) rates and to improve oncological outcomes. Ductal carcinoma in situ (DCIS) can be present adjacent to invasive breast cancer (IBC), especially in HER2-positive IBC. DCIS was previously considered to be insensitive to NST. Consequently, mastectomy rates are higher in IBC with adjacent DCIS. Recent studies have shown that DCIS can be sensitive to NST, however, only small populations were investigated. Therefore, the aim of this study was to determine the rate of complete response of adjacent DCIS in HER2-positive IBC and to assess the potential influence of clinicopathological variables in a nationwide cohort. Methods All women diagnosed with HER2-positive IBC, treated with NST and surgery between January 2010 and December 2019, were selected from the Netherlands Cancer Registry (NCR). Of these patients, all pre-NST biopsy and postoperative specimen pathology reports were obtained from PALGA, the Dutch Pathology Registry, and assessed for presence of DCIS. Response of DCIS was defined as absence of DCIS in postoperative pathology when a DCIS component was present in the pre-NST biopsy. Clinicopathological factors associated with DCIS response were assessed using logistic regression analyses. Results In total, 5834 patients were included, of whom 1443 (24.7%) had a DCIS component in the pre-NST biopsy. Mastectomy rates were higher in IBC with adjacent DCIS compared to IBC without adjacent DCIS in the pre-NST biopsy (53.6% versus 41.0%, p< 0.001). Of these 1443 patients, 743 (51.5%) showed complete response of the DCIS component. Complete response of DCIS occurred more frequently in patients who also had a complete response of IBC (63.4% versus 33.8%, p< 0.001). Multivariable logistic regression analysis showed ER negative IBC (OR 1.79; 95% CI 1.33-2.42) and treatment with HER2-targeted therapy (OR 5.97; 95% CI 1.82-19.55) to be independently associated with complete response of DCIS. Conclusion More than half of HER2-positive IBC patients with adjacent DCIS in the pre-NST biopsy showed a complete response of the DCIS component to NST. Complete response of DCIS should be considered, especially in ER-negative HER2-positive IBC and in case of complete response of IBC. Future studies should investigate the evaluation of DCIS response by imaging and the possibility of increasing breast-conserving surgery rates. Citation Format: Roxanne Ploumen, Eva Claassens, Loes Kooreman, Kristien Keymeulen, Maartje van Kats, Suzanne Gommers, Sabine Siesling, Thiemo van Nijnatten, Marjolein Smidt. Complete response of ductal carcinoma in situ to neoadjuvant systemic therapy in HER2-positive invasive breast cancer patients: a nationwide analysis [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 P4-06-02.

Purpose Ductal carcinoma in situ (DCIS) is present in more than half of HER2-positive invasive breast cancer (IBC). Recent studies show that DCIS accompanying HER2-positive IBC can be completely eradicated by neoadjuvant systemic therapy (NST). Our aim was to determine the percentage of pathologic complete response of the DCIS component in a nationwide cohort and to assess associated clinicopathologic variables. Furthermore, the impact on surgical treatment after NST was investigated. Methods Women diagnosed with HER2-positive IBC, treated with NST and surgery, between 2010-2020, were selected from the Netherlands Cancer Registry. Pre-NST biopsy and postoperative specimen pathology reports were obtained from the Dutch Nationwide Pathology Databank, and assessed for presence of DCIS. Clinicopathologic factors associated with DCIS response were assessed using logistic regression analyses. Results A DCIS component was present in the pre-NST biopsy in 1443 of the 5834 included patients (24.7%). Pathologic complete response of the DCIS component was achieved in 743 (51.5%) of these patients. Complete response of DCIS occurred more frequently in case of complete response of IBC (63.4% versus 33.8%, pConclusion Pathologic complete response of DCIS occurred in 51.5% of HER2-positive IBC patients and was associated with ER-negative IBC and complete response of IBC. Future studies should investigate imaging evaluation of DCIS response to improve surgical decision making.

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p

Background: For patients with ductal carcinoma in situ (DCIS), data about contralateral breast cancers detected by MRI at primary diagnosis and the impact of MRI use on the incidence and stage of contralateral breast cancers during follow-up are scarce. Methods: We selected all women diagnosed with a primary DCIS in the Netherlands in 2011-2015 from the Netherlands Cancer Registry. The synchronous and metachronous detection of contralateral DCIS and contralateral invasive breast cancer was assessed for patients who did receive an MRI upon primary diagnosis (MRI group) and for an age-matched control group without MRI. Incidence of contralateral disease during follow-up was calculated using competing risk methods.Results: Of the 8486 patients diagnosed with primary DCIS, 1571 (19%) received an MRI. In the MRI group, 0.8% of patients were diagnosed with a synchronous contralateral DCIS and 1.3% with synchronous contralateral invasive breast cancer. Median follow-up time was 6.4 years (IQR: 5.1-7.6). The estimated five-year cumulative incidence of synchronous plus metachronous contralateral DCIS was 2.0% (95% CI: 1.4%-2.8%)) for the MRI group and 0.9% (95% CI: 0.5%-1.5%) for the age-matched control group. The five-year cumulative incidence of contralateral invasive breast cancer was 3.5% (95% CI: 2.7%-4.5%) for the MRI group and 2.3% (95% CI: 1.6%-3.1%) for the age-matched control group. In patients aged Citation Format: Kristien Keymeulen, Sandra Geurts, Loes Kooreman, Lucien Duijm, Sanne Engelen, Sigrid Vanwetswinkel, Ernest Luiten, Sabine Siesling, Adri Voogd, Vivianne Tjan-Heijnen. Contralateral breast cancers detected by pre-operative MRI in patients diagnosed with DCIS: Whart do they mean? [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 P3-03-21.

The enzyme type 1 17β-hydroxysteroid dehydrogenase (17β-HSD-1), responsible for generating active 17β-estradiol (E2) from low-active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition. In this study, we explored the possibility of inhibiting 17β-HSD-1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17β-HSD-1 similar to human tissues. In these cells, HPLC analysis showed that 17β-HSD-1 activity could be blocked by a specific 17β-HSD-1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17β-HSD-1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17β-HSD-1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17β-HSD-1-negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17β-HSD-1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17β-HSD-1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17β-HSD-1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17β-HSD-1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17β-HSD-1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.