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Purpose: Estrogen receptor (ER) expression predicts response to endocrine therapy and is a prognostic biomarker. However, no ER-associated biomarker is able to identify patients with particularly favorable outcome among ER+ tumors. We investigated the value of ESR1 amplification in predicting long-term outcome in tamoxifen-treated postmenopausal women with early breast cancer with and without nodal involvement. Patients and Methods: 394 patients with ER+ breast cancer (235 node-negative, 159 patients node- positive), who had received adjuvant tamoxifen for 5 years in the prospective randomized ABCSG-06 trial, and in whom FFPE tumor tissue was available, were included in this analysis. ER alpha immunoreactivity was evaluated using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis. Results: Focal ESR1 amplification was detected in 187 (47%) tumors, and was associated with a favorable outcome. After a median follow-up of 10 years, women with focal ESR1 amplification had a significantly longer distant recurrence-free survival (DRFS; adjusted HR 0.48; 95% CI 0.26-0.91; p=0.02) and breast cancer-specific survival (BCSS; adjusted HR 0.47; CI 0.27-0.80; p=0.01) compared to women without ESR1 amplification. The association between ESR1 amplification and improved DRFS and BCSS was only found in node-positive tumors, but not in nodal-negative tumors. ER alpha immunoreactivity, evaluated by Allred score, correlated significantly with focal ESR1 amplification (p< 0∙0001; Chi-squared test), but without prognostic significance. Conclusion: We suggest focal ESR1 amplification as predictor of improved long-term outcome in postmenopausal women with node-positive ER+ early breast cancer. Citation Format: Christian F. Singer, Frederik Holst, Stefan Steurer, Eike Burandt, Sigurd Lax, Raimund Jakesz, Margaretha Rudas, Herbert Stöger, Richard Greil, Guido Sauter, Martin Filipits, Ronald Simon, Michael Gnant. Focal ESR1 gene amplification is an independent prognostic marker in postmenopausal patients with endocrine-responsive 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 P2-11-15.

Funding Information: The authors thank ESGO, ESTRO, and ESP for their support. The authors also thank the 155 international reviewers (physicians and patient representatives, see Appendix 2 in Online Supplemental File 2) for their valuable comments and suggestions. The authors thank the ESGO office, especially Kamila Macku, Tereza Cicakova, and Kateřina Šibravová, provided invaluable logistical and administrative support throughout the process. The development group (including all authors) is collectively responsible for the decision to submit for publication. DC (chair), JL (chair), MRR (chair) and FP (methodologist) wrote the first draft of the manuscript. All other contributors have actively given personal input, reviewed the manuscript, and have given final approval before submission. DC is responsible for the overall content as the guarantor. Initiated through the ESGO the decision to develop multidisciplinary guidelines was made jointly by the ESGO, ESTRO, and ESP. The ESGO provided administrative support. The ESGO, ESTRO and ESP are nonprofit knowledgeable societies. *These guidelines were developed by ESGO, ESTRO and ESP and are published in the Int J Gynecol Cancer, Radiother Oncol and Virchows Archiv. CCh has reported advisory boards for GSK, MSD and EISAI; SFL has reported advisory boards for MSD, GSK, AstraZeneca and Novartis; DL has reported consultant honoria from AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Amgen, Seagen and PharmaMar, advisory boards for AstraZeneca, Merck Serono, Seagen, Immunogen, Genmab, Oncoinvest, Corcept and Sutro, research institutional funding from Clovis Oncology, GSK, MSD and PharmaMar, research sponsored by AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Roche, Seagen and Novartis, and speakers’ bureau activities for AstraZeneca, Clovis Oncology, GSK, MSD and PharmaMar; UM has reported advisory boards for AstraZeneca (Steering committee member for CALLA Study); RN has reported research grants from Elekta, Varian, Accuray, Dutch Research Council, and Dutch Cancer Society; AO has reported personal fees for advisory board membersip from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, F. Hoffmann-La Roche, Genmab/Seagen, GSK, ImmunoGen, Itheos, Merck Sharp & Dohme de Espana, SA, Mersana Thereapeutics, Novocure, PharmaMar, piIME Oncology, Roche, Sattucklabs, Sutro Biopharma and Tesaro, and personal fees for travel/accomodation from AstraZeneca, PharmaMar and Roche; DQ has reported advisory boards for Mimark inc; MPS has reported research grants and personal fees for workshops from Elekta AB; DC, MRR, FP, CC, AF, DF, DJK, FJ, CK, PM, RN, FPec, JP, SR, AS, VS, KT, IZ and JCL have reported no conflicts of interest. Not commissioned; internally peer reviewed. Not applicable. Not applicable. David Cibula, Maria Rosaria Raspollini, François Planchamp, Carlos Centeno, Cyrus Chargari, Ana Felix, Daniela Fischerova, Daniela Jahn-Kuch, Florence Joly, Christhardt Kohler, Sigurd F. Lax, Domenica Lorusso, Umesh Mahantshetty, Patrice Mathevet, Raj Naik, Remi Nout, Ana Oaknin, Fedro Peccatori, Jan Persson, Denis Querleu, Sandra Rubio, Maximilian Paul Schmid, Artem Stepanyan, Valentyn Svintsitskyi, Karl Tamussino, Ignacio Zapardiel, Jacob Christian Lindegaard. All data relevant to the study are included in the article or uploaded as supplementary information. Funding Information: CCh has reported advisory boards for GSK, MSD and EISAI; SFL has reported advisory boards for MSD, GSK, AstraZeneca and Novartis; DL has reported consultant honoria from AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Amgen, Seagen and PharmaMar, advisory boards for AstraZeneca, Merck Serono, Seagen, Immunogen, Genmab, Oncoinvest, Corcept and Sutro, research institutional funding from Clovis Oncology, GSK, MSD and PharmaMar, research sponsored by AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Roche, Seagen and Novartis, and speakers’ bureau activities for AstraZeneca, Clovis Oncology, GSK, MSD and PharmaMar; UM has reported advisory boards for AstraZeneca (Steering committee member for CALLA Study); RN has reported research grants from Elekta, Varian, Accuray, Dutch Research Council, and Dutch Cancer Society; AO has reported personal fees for advisory board membersip from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, F. Hoffmann-La Roche, Genmab/Seagen, GSK, ImmunoGen, Itheos, Merck Sharp & Dohme de Espana, SA, Mersana Thereapeutics, Novocure, PharmaMar, piIME Oncology, Roche, Sattucklabs, Sutro Biopharma and Tesaro, and personal fees for travel/accomodation from AstraZeneca, PharmaMar and Roche; DQ has reported advisory boards for Mimark inc; MPS has reported research grants and personal fees for workshops from Elekta AB; DC, MRR, FP, CC, AF, DF, DJK, FJ, CK, PM, RN, FPec, JP, SR, AS, VS, KT, IZ and JCL have reported no conflicts of interest. Publisher Copyright: © 2023 ESGO, ESTRO, ESP In 2018, the European Society of Gynecological Oncology (ESGO) jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published evidence-based guidelines for the management of patients with cervical cancer. Given the large body of new evidence addressing the management of cervical cancer, the three sister societies jointly decided to update these evidence-based guidelines. The update includes new topics to provide comprehensive guidelines on all relevant issues of diagnosis and treatment in cervical cancer. To serve on the expert panel (27 experts across Europe) ESGO/ESTRO/ESP nominated practicing clinicians who are involved in managing patients with cervical cancer and have demonstrated leadership through their expertise in clinical care and research, national and international engagement, profile, and dedication to the topics addressed. To ensure the statements were evidence based, new data identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Before publication, the guidelines were reviewed by 155 independent international practitioners in cancer care delivery and patient representatives. These updated guidelines are comprehensive and cover staging, management, follow-up, long-term survivorship, quality of life and palliative care. Management includes fertility sparing treatment, early and locally advanced cervical cancer, invasive cervical cancer diagnosed on a simple hysterectomy specimen, cervical cancer in pregnancy, rare tumors, recurrent and metastatic diseases. The management algorithms and the principles of radiotherapy and pathological evaluation are also defined. publishersversion published

Funding Information: Open access publishing supported by the National Technical Library in Prague. Funding Information: The authors thank ESGO, ESTRO, and ESP for their support. The authors also thank the 155 international reviewers (physicians and patient representatives, see Appendix 2 ) for their valuable comments and suggestions. The authors thank the ESGO office, especially Kamila Macku, Tereza Cicakova, and Kateřina Šibravová, provided invaluable logistical and administrative support throughout the process. Publisher Copyright: © 2023, ESGO, ESTRO, ESP. In 2018, the European Society of Gynecological Oncology (ESGO) jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published evidence-based guidelines for the management of patients with cervical cancer. Given the large body of new evidence addressing the management of cervical cancer, the three sister societies jointly decided to update these evidence-based guidelines. The update includes new topics to provide comprehensive guidelines on all relevant issues of diagnosis and treatment in cervical cancer. To serve on the expert panel (27 experts across Europe) ESGO/ESTRO/ESP nominated practicing clinicians who are involved in managing patients with cervical cancer and have demonstrated leadership through their expertise in clinical care and research, national and international engagement, profile, and dedication to the topics addressed. To ensure the statements were evidence based, new data identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Before publication, the guidelines were reviewed by 155 independent international practitioners in cancer care delivery and patient representatives. These updated guidelines are comprehensive and cover staging, management, follow-up, long-term survivorship, quality of life and palliative care. Management includes fertility sparing treatment, early and locally advanced cervical cancer, invasive cervical cancer diagnosed on a simple hysterectomy specimen, cervical cancer in pregnancy, rare tumors, recurrent and metastatic diseases. The management algorithms and the principles of radiotherapy and pathological evaluation are also defined. publishersversion published

PDF file - 868K, Ratio bin distributions for CTC12 (a) and CTC03 (b) from patient #6. The large bin 13 peak indicates the frequency of oligonucleotides with balanced ratio values. The bins to the right of 13 represent the bins for oligonucleotides with deleted, the bins to the left oligonucleotides with increased values. (a) In CTC12 only one of the bins for deleted values was increased (i.e. bin 15), suggesting that this cell is diploid. In a diploid cell the log2 ratio for balanced values ranges from 0.295 to -0.293 and therefore extends to bins adjacent to 13, which is reflected by the small increases in the bins 12 and 14. The peaks at bins 11 and 12 reflect trisomies (i.e. a 3:2 ratio or an integer copy number of 3), the peak at 9 indicates tetrasomies (i.e. 4:2) or 4 copies). (b) CTC03 had clearly more discrete deleted copy number states visible at bins 15 to 18, suggesting that this cell is tetraploid. In a tetraploid cell the log2 ratio range for balanced values is narrower (i.e. 0.161 to -0.208) as in a diploid cell, which is reflected in the almost empty bins 12 and 14. Bin 15 represents oligonucleotides with ratio values translating to 3 copies, bins 16 and 17 to two copies and bin 18 to one copy. Bin 10 represents 5 copies, bins 8 and 9 six copies, bin 7 seven copies, and bin 4 eight copies.

PDF file - 95K, List of 68 genes, which, according to the COSMIC database, are frequently mutated in colorectal carcinoma (CRC) and analyzed in our study.

PDF file - 1303K, Evaluation of available material from patient #9. (a-b) Array CGH profiles of the primary tumor (a) and metastasis (peritoneal carcinomatosis) (b). Regarding the color bar codes please see legend to Supp. Fig. 2.

PDF file - 188K, Sequencing of UCR41 and flanking regions: UCR41 is a 217-bp-long ultra-conserved region depicted in dark green. The gray bar indicates the extremely conserved sequence. The region is flanked by two SNPs that are frequent in the European population (blue arrows). The black curve indicates the mutability, which is higher in non-conserved regions compared with conserved segments. The black bars illustrate the 5 overlapping amplicons used for amplification. Mutations identified in our samples are indicated with red arrows. The genomic coordinates refer to the hg18 assembly of the human genome. (The graph is reproduced with permission from De Grassi et al.)

PDF file - 346K, Analysis of CTC03 of patient #22: The array-CGH ratio profile demonstrates losses on chromosomes 3, 4, 5, 8p, and 18 and gains on chromosomes 7p, 17q, and 20.

PDF file - 940K, Evaluation of available material from patient #6. (a-b) Array CGH profiles of the primary tumor (a) and metastasis (b). The multicolor bar codes at the top or bottom of the ratio profiles illustrate the results obtained during the iterative calculations with various window sizes, the single green and red bars summarize the regions which were gained or lost based on all calculations (Supplementary Methods). Black parts in the profile represent balanced regions, lost regions appear in red and gained regions in green.

PDF file - 3383K, Calculation of different integer copy number profiles for CTC03 from patient #6 assuming diploidy (a), triploidy (b), or tetraploidy (c) and the respective array CGH profile (d).

PDF file - 231K, Evaluation of available material from patient #6. (c) Integer copy number profiles of CTC14.

PDF file - 92K, Identification of mutations in cancer candidate (CAN) genes in patient samples using next-generation sequencing. Mutations that are shared between primary tumor and/or metastasis and/or CTCs are highlighted in bold.

Determination of microsatellite instability (MSI) and mismatch repair deficiency (MMRD), respectively, in endometrial carcinomas (ECs) is important for diagnostic and prognostic purposes, identification of Lynch syndrome carriers, and selection of patients for immunotherapy. The Idylla™ MSI assay is fully automated, does not require non-tumoral tissue, and can be performed in about 150 min. Two hundred forty-two formalin-fixed paraffin-embedded (FFPE) EC samples from 7 international centers were tested by the Idylla™ MSI assay and compared to the Promega™ MSI Analysis System and immunohistochemistry (IHC) for MMR proteins. The cases were selected with an enrichment of MSI EC to around 40%. Concordance was 87.5% between the Idylla™ MSI assay and IHC and 88.58% between IHC and Promega™ MSI assay. Concordance between Idylla™ and Promega™ MSI assays was 89.91%. Discordant results occurred more frequently in cases with MSH6 or PMS2 deficiency. Invalid cases occurred with the three techniques (IHC, 7.00%; Promega™ MSI assay, 5.37%; and Idylla™ MSI assay, 2.47%). The concordance rate between Idylla™ MSI assay and the other 2 methods increased to 88.83% for IHC and to 91.22% for the Promega™ MSI assay when the cutoff of instability in the scoring system was moved from 0.5 to 0.3. The Idylla™ MSI assay is a rapid and highly concordant test for MSI in EC. Modification of the Idylla™ scoring system could increase the sensitivity and specificity of the MSI assay for EC analysis.

Papillary lesions of the breast represent a heterogeneous group of lesions including benign papillomas, papillomas with focal epithelial atypia, fully fledged ductal carcinoma in situ (DCIS) or lobular neoplasia, papillary DCIS, encapsulated papillary carcinomas without or with invasion, solid papillary carcinomas, and invasive papillary carcinomas. A micropapillary pattern characterized by lack of fibrous stalks within the papillae is observed in micropapillary DCIS and invasive micropapillary carcinoma. In addition, a variety of other rare breast lesions reveals a papillary architecture such as tall cell carcinoma with reversed polarity (TCCRP) and mucinous cystadenocarcinoma, adenomyoepithelioma, and secretory carcinoma. In addition, benign lesions such as usual ductal hyperplasia, apocrine metaplasia, gynecomastia, and juvenile papillomatosis may show a papillary or micropapillary architecture. Fragments of a benign papilloma in a breast biopsy are considered a lesion of uncertain malignant potential (B3 in the European classification) and excision is mostly recommended. Although the knowledge about molecular pathology of papillary breast lesions has increased, there is not sufficient evidence for diagnostically useful molecular features, yet. The aim of this review is to provide an update on papillary and micropapillary lesions with emphasis on problematic areas for daily diagnostic work including biopsies. ispartof: VIRCHOWS ARCHIV vol:480 issue:1 pages:65-84 ispartof: location:Germany status: published