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5. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial

Author

Vassiliki Karantza, Shparyk Yaroslav, Sumrall Bradley, Javier Cortes, Iwata Hiroji, Kolesnik Oleksii, Ahn Jin Hee, Harbeck Nadia, Prausova Jana, Song Xinni, Berzoy Oleksandr, Mena Raul, Osaki Akihiko, Kahan Zsuzsanna, Simon Michael, Ozguroglu Mustafa, Chmielowska Ewa, Tsugawa Koichiro, Tsao Chao-Jung, Ozyilkan Ozgur, Nowecki Zbigniew, Fadeeva Natalia, Kaen Diego, Garcia Saenz Jose, Porter David, Ngan Kai Cheong Roger, Sherene Loi, Bermejo de las Heras Begona, Turner Nicholas, David W. Cescon, Hope S. Rugo, Oliff Ira, Kelly Catherine, Barrios Carlos, Cole Scott, Shevnya Sergii, Seock-Ah Im, Hoskins Kent, Komisarenko Hanna, Yavuz Sinan, Chaudhry Madhu, Sagara Yasuaki, Brust Leandro, Chan Steve, Gomez Villanueva Angel, Gallardo Carlos, Watanabe Junichiro, Ishikawa Takashi, Schleider Michael, Salas Claudio, Hardy-Bessard Anne-Claire, Erhan Gokmen, Adamchuk Hryhoriy, Beelen Karin, Holeckova Petra, Szczylik Cezary, Fujii Takaaki, Nakamura Seigo, Aruga Tomoyuki, Gokmen Erhan, Jing Zhao, Hiroji Iwata, Molinas Mandel Nil, Gogineni Keerthi, Im Seock-Ah, Zifang Guo, Loi Sherene, Costa Fabiano, Forstmeyer Dirk, Kosaka Yoshimasa, Gomez Diaz Alvaro, Ponomarova Olga, Wimberger Pauline, DAlessio Antonietta, Suzuki Eiji, Blohmer Jens-Uwe, Kowalwszyn Ruben, Molina Matias, Clingan Philip, Yamamoto Yutaka, Sabanathan Dhanusha, Gursel Aktan, Vynnychenko Ihor, Ferrario Cristiano, Schumann Raquel Von, Trukhin Dmytro, Arkosy Peter, Tseng Ling-Ming, Moore Susan, Gunduz Seyda, Stampleman Laura, de Freitas Junior Ruffo, Acevedo Alejandro, Lipatov Oleg, Niikura Naoki, Norikazu Masuda, Rusyn Andrii, Kral Zdenek, Crown John, Yamamoto Naohito, Jakobsen Erik, Blau Sibel, Bustam Anita, Zamora Adelantado Esther, Nanda Rita, Omene Coral, Arslan Cagatay, Kwong Ava, Teixeira Luis, Jensen Jeanette, Ito Yoshinori, Siegel Robert, Mastura Md Yusof, Nowakowska-Zajdel Ewa, Miyoshi Yasuo, Yu Joanne, Tuthill Mark, Mukhametshina Guzel, Matsumoto Koji, Gion Maria, Melichar Bohuslav, Desmoulins Isabelle, Moiseyenko Vladimir, Zurawski Bogdan, Carlos Gallardo, Lorincz Tamas, Cruz Jurado Josefina, Bondarenko Igor, Kaczerowsky Flores de Sousa Anna, Yamauchi Teruo, Loutfi Randa, Esther Holgado, Holgado Esther, Twelves Christopher, Streb Joanna, Tanabe Yuko, Tarnawski Rafal, Morales-Vasquez Flavia, Park Kwong Hwa, Csoszi Tibor, Meshcheryakov Andrey, Scalabrini Neto Antonio Orlando, Oleg Lipatov, Iwasa Tsutomu, Ricevuto Enrico, Tamura Kenji, Patson Brian, Liu Mei-Ching, Cinieri Saverio, Loibl Sibylle, Tjan-Heijnen Vivianne, Glavicic Vesna, Panwalkar Amit, Hargis Jeffrey, Kryzhanivska Anna, Yusof Mastura, O'Reilly Seamus, Rubovszky Gabor, Irvin William, Takahashi Masato, Ohtani Shoichiro, Peter Schmid, Carlos H. Barrios, Sanchez Cesar, Zbigniew Nowecki, Arkhipov Alexander, Chung Michael, Liu Chien-Ting, Mukai Hirofumi, Marco Torregroza Otero, Charpentier Danielle, Park-Simon Tjoung-Won, Lee Keun Seok, Leshchenko Iurii, Huang Chiun-Sheng, Tsai Michaela, Panella Timothy, Petrakova Katarina, MacPherson Iain, Schmid Peter, Baron-Hay Sally, Ursol Grygorii, Lacerda Domicio Carvalho, Cobb Patrick, Sanchez Jesus, Park Yeon Hee, Reyes Contreras Jessica, Fein Luis, Hegg Roberto, Diamond Jennifer, Huober Jens, Rugo Hope, Rybalova Irina, de la Cruz Merino Luis, Linnet Soren, Inoue Kenichi, Wheatley Duncan, Cescon David, Cicin Irfan, Gombos Andrea, Bonnefoi Herve, Nasonova Alla, Taylor Donatienne, Martinez Rodriguez Jorge, Valdes-Albini Frances, Juarez Ramiro Alejandro, Cortes Javier, Lu Janice, Silva Felipe, Lueftner Diana, Landherr Laszlo, Gomez Abuin Gonzalo, Yanez Eduardo, Rocha Roberto Odebrecht, Chow Louis, Otchenash Natalya, Radecka Barbara, Kolesnik Olena, Basaran Gul, Kurbacher Christian, Mahr Karoly, Goncalves Anthony, Begbie Stephen, Graham Janine, Fasching Peter, Varela Mirta, and Lissa Fernando Cezar Toniazzi

Subjects
Oncology, double blind procedure, pharmacist, CD274 protein, human, hazard ratio, 0302 clinical medicine, middle aged, Antineoplastic Combined Chemotherapy Protocols, cancer survival, comparative study, education.field_of_study, progression free survival, adult, drug effect, gemcitabine, clinical trial, General Medicine, nausea, anemia, Progression-Free Survival, priority journal, immunological antineoplastic agent, thyroiditis, pembrolizumab, metastatic breast cancer, neoadjuvant chemotherapy, medicine.medical_specialty, Antineoplastic Agents, intention to treat analysis, Article, skin manifestation, 03 medical and health sciences, Breast cancer, cancer combination chemotherapy, neutropenia, Humans, Progression-free survival, human, education, protein expression, cancer immunotherapy, treatment response, Interim analysis, medicine.disease, major clinical study, tumor recurrence, Carboplatin, programmed death 1 ligand 1, drug efficacy, multicenter study, chemistry, monoclonal antibody, randomized controlled trial, fatigue, drug tolerability, cancer patient, age distribution, drug safety, colitis, clinical outcome, Triple Negative Breast Neoplasms, Pembrolizumab, 030204 cardiovascular system & hematology, B7-H1 Antigen, Placebos, chemistry.chemical_compound, paclitaxel, Antineoplastic Agents, Immunological, Outcome Assessment, Health Care, 030212 general & internal medicine, antineoplastic agent, cancer adjuvant therapy, Eastern Cooperative Oncology Group performance status, female, carboplatin, sodium chloride, immunohistochemistry, medicine.drug, interactive voice response system, alanine aminotransferase, overall survival, Population, Antibodies, Monoclonal, Humanized, Double-Blind Method, Internal medicine, medicine, follow up, hyperthyroidism, pneumonia, controlled study, Taxane, phase 3 clinical trial, business.industry, hypertransaminasemia, alopecia, Gemcitabine, human tissue, cancer recurrence, functional status assessment, triple negative breast cancer, placebo, inoperable cancer, pathology, hypothyroidism, Neoplasm Recurrence, Local, business, metabolism, Follow-Up Studies
Abstract

Background: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine–carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ?1 or, Breast Cancer Research Foundation, BCRF; Pfizer; AstraZeneca; Merck; Roche; Samsung; Merck Sharp and Dohme, MSD; Eisai, JC reports personal fees and research funding paid to his institution from Roche, AstraZeneca, Merck Sharp & Dohme, and Eisai; personal fees from Celgene, Cellestia, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, GlaxoSmithKline, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Kyowa Kirin, Novartis, Pfizer, Samsung Bioepis; research funding paid to his institution from Ariad Pharmaceuticals, Bayer Healthcare, F Hoffman-La Roche, Guardanth Health, Piqur Therapeutics, Puma C, and Queen Mary University of London, outside the submitted work. In addition, JC has a MedSIR patent pending. DWC reports research support from Merck during the conduct of the study; research support paid to his institution from Merck, Pfizer, and GlaxoSmithKline; personal fees from Merck, Roche–Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Puma, Agenda, Exact Sciences, and Dynamo Therapeutics, outside the submitted work. In addition, DWC has a Biomarkers of TTK inhibitors patent pending. HSR reports funding for sponsored studies paid to the University of California San Francisco from Pfizer, Novartis, Lilly, Roche–Genentech, Macrogenics, OBI, Merck, Eisai, Immunomedics, Daiichi Sankyo, Seattle Genetics, and Odonate; travel support for educational meetings from Daiichi Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and Macrogenics; and consulting fees from Samsung and Puma, outside the submitted work. S-AI reports grants from AstraZeneca, Eisai, Pfizer, Roche, and Daewoong; an advisory role for AstraZeneca, Amgen, Eisai, Hanmi, Novartis, Lily, MedPacto, Pfizer, and Roche; and travel expenses for presentation from Novartis, outside the submitted work. CG reports Advisory Board fees from Merck Sharp & Dohme and Roche; and speaker's bureau fees from Bristol Myers Squibb and AstraZeneca, outside the submitted work. CHB reports grants and fees from Merck Sharp & Dohme for clinical research consulting during the conduct of the study; consulting–advisory role fees from Boehringer Ingelheim, GlaxoSmithKline, and Bayer; consulting–advisory role fees and grants for clinical research from Novartis, Pfizer, Roche–Genentech, Eisai, Merck Sharp & Dohme, and AstraZeneca; grants for clinical research from Abbvie, Amgen, Astellas Pharma, Bristol Myers Squibb, Celgene, Covance, Lilly, Medication, Merck Serono, and PharmaMar; grants for academic research projects from CPO, Pontificia Universidade Católica do Rio Grande do Sul, Latin American Cooperative Oncology Group, Grupo Brasileiro Estudos Câncer Mama, and Instituto Nacional de Câncer-Brazil, outside the submitted work. HI reports a grant from Merck Sharp & Dohme during the conduct of the study; honoraria and consulting fees from Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Eisai, and Chugai; and a grant from Chugai, outside the submitted work. NM reports honoraria and research funding paid to his institution from Chugai, AstraZeneca, Pfizer, Eli-Lilly, Eisai, Takeda, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, and Daiichi Sankyo, outside the submitted work. EG reports non-financial support from Merck Sharp & Dohme during the conduct of the study; honoraria, consulting–advisory fees and meeting support from Novartis, Roche, Bristol Myers Squibb, and Pfizer; and honoraria from AstraZeneca and Astellas, outside the submitted work. SL reports research funding or consulting fees paid to her institution from Bristol Myers Squibb, Roche–Genentech, Puma Biotechnology, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, Eli Lilly, Aduro Biotech, GI Therapeutics, AstraZeneca, and GlaxoSmithKline; and non-remunerated consultancy for Bristol Myers Squibb, Roche–Genentech, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, and AstraZeneca, outside the submitted work. In addition, SL is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. ZG, JZ, GA, and VK are employees of Merck Sharp & Dohme and own stock or stock options in Merck. PS reports consultancy fees from Pfizer, AstraZeneca, Novartis, Roche, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; consultancy fees to his spouse from Genentech and Roche; and grants or funding to his institution from Roche, Genentech, Oncogenex, Novartis, Astellas, and AstraZeneca, outside the submitted work. All other authors declare no competing interests., The authors thank the patients, their families and caregivers for participating in this trial, all of the investigators and site personnel, and the following employees of Merck Sharp & Dohme: Wilbur Pan, Deborah Card, Eleanor Readinger, Shana Hamm, Roger Maxwell, and Krystal Bourdon, for collection of data, supervision of research, provision of study materials or patients or administrative or logistical support; Aline Galvao, for collection of data, supervision of research, administrative or logistical support, and review of imaging data related to the primary end point; Donna Letizia, for collection of data and imaging expertise; Jennifer Kimmel, for study management; Mercedes Bustamante, for data collection and management; Xuan Zhou and Madhusudhan Reddy Papasani, for statistical expertise; Christine McCrary Sisk, for medical writing and editorial assistance; and Joseph C Naggar and Michele McColgan, for administrative or logistical support.

Published
2020

6. Recommendation and Acceptance of Counselling for Familial Cancer Risk in Newly Diagnosed Breast Cancer Cases.

Author

Kast, Karin, Häfner, Julia, Schröck, Evelin, Jahn, Arne, Werner, Carmen, Meisel, Cornelia, and Wimberger, Pauline

Subjects
BREAST tumor diagnosis, BREAST tumor risk factors, ADJUVANT chemotherapy, ACADEMIC medical centers, CANCER chemotherapy, RISK assessment, GENETIC counseling, BREAST tumors, FAMILY history (Medicine)
Abstract

Background: In clinical routine, not every patient who is offered genetic counselling and diagnostics in order to investigate a familial cancer risk predisposition opts for it. Little is known about acceptance of counselling and testing in newly diagnosed breast cancer cases in Germany. Methods: All primary breast cancer cases and patients with DCIS (ductal carcinoma in situ) treated at the University Hospital of Dresden between 2016 and 2019 were included. The number of tumor board recommendations for genetic counselling on the basis of the GC-HBOC risk criteria was recorded. Acceptance was analyzed by number of cases with counselling in the GC-HBOC-Center Dresden. Results: Of 996 primary breast cancer and DCIS cases, 262 (26.3%) were eligible for genetic counselling. Recommendation for genetic counselling was accepted by 64.1% (168/262). Of these 90.5% (152/168) opted for molecular genetic analysis. The acceptance rate for counselling increased between 2016 and 2019 from 58.3 to 72.6%. Altogether, 20.4% (31/152) patients were found to carry a pathogenic variant in the breast cancer genes BRCA1 or BRCA2. Conclusion: Acceptance of recommendation is increasing as clinical consequences augment. Optimization in providing information about hereditary cancer risk and in accessibility of counselling and testing is required to further improve acceptance of recommendation. [ABSTRACT FROM AUTHOR]

Published
2022
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7. Patient-Reported Satisfaction after Prophylactic Operations of the Breast.

Author

Keller, Katja, Meisel, Cornelia, Grübling, Nannette, Petzold, andrea, Wimberger, Pauline, and Kast, Karin

Subjects
BREAST tumors, BREAST tumor risk factors, SURGICAL flaps, GENEALOGY, GENETIC techniques, INTERVIEWING, LONGITUDINAL method, MASTECTOMY, PREVENTIVE medicine, GENETIC mutation, HEALTH outcome assessment, PATIENT satisfaction, PUBLIC health surveillance, QUALITY of life, RISK assessment, SURGICAL complications, PLASTIC surgery, SURVEYS, BRCA genes, TREATMENT effectiveness, RETROSPECTIVE studies, PATIENT decision making, GENETICS
Abstract

Background: Prophylactic mastectomies in carriers of mutations in BRCA1 or BRCA2 are becoming increasingly more accepted. We investigated the outcome after prophylactic mastectomy, especially regarding satisfaction with the procedure, in a monocenter study. Methods:BRCA1/2 mutation carriers and non-carriers with elevated pedigree-based cancer risk were followed prospectively in a structured surveillance program between 2000 and 2017. A retrospective telephone survey was conducted among all patients with documented prophylactic mastectomy. Complications and satisfaction with the decision for prophylactic mastectomy were recorded. Results: 39 patients who opted for a prophylactic mastectomy (38 BRCA1/2 mutation carriers and 1 non-carrier) were interviewed. Mostly nipple-sparing mastectomy with reconstruction was performed (87%). Half of the patients (22/39; 56.4%) had a history of unilateral breast cancer. The median time since prophylactic mastectomy was 5.6 years. While 61.5% did not report any complications, flap loss was seen in 15% (3/20) and moderate limitations in everyday life were present in 20% (7/35). An improvement in quality of life was noticed by 82% after prophylactic mastectomy and no patient expressed regret with regard to the decision. Conclusions: Prophylactic mastectomy is a procedure with risk for long-term complications in some cases. Our results confirm high satisfaction with the decision and improved quality of life. [ABSTRACT FROM AUTHOR]

Published
2019
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8. Impact of disease progression on health-related quality of life in patients with metastatic breast cancer in the PRAEGNANT breast cancer registry.

Author

Müller, Volkmar, Nabieva, Naiba, Häberle, Lothar, Taran, Florin-Andrei, Hartkopf, Andreas D., Volz, Bernhard, Overkamp, Friedrich, Brandl, Anna Lisa, Kolberg, Hans-Christian, Hadji, Peyman, Tesch, Hans, Ettl, Johannes, Lux, Michael P., Lüftner, Diana, Belleville, Erik, Fasching, Peter A., Janni, Wolfgang, Beckmann, Matthias W., Wimberger, Pauline, and Hielscher, Carsten

Subjects
METASTATIC breast cancer, DISEASE progression, BREAST cancer, QUALITY of life, PROGRESSION-free survival
Abstract

Objectives Improved progression-free survival is considered as treatment goal for patients with metastatic breast cancer (MBC) since it is assumed to delay or prevent deterioration of quality of life. Aim of our analysis was to examine the influence of disease progression on health-related quality of life (HRQoL). Materials and methods The PRAEGNANT study comprises a real-life registry for patients with MBC. HRQoL was assessed with the EORTC-QLQ-C30 Version 3.0 questionnaire at study entry and every 3 months thereafter. The primary endpoint was minimally important deterioration (MID) in global HRQoL score by ≥ five points between baseline and any follow-up assessment. A logistic regression model was built with MID (yes/no) at a follow-up timepoint as outcome variable and several covariates as predictors. Results In total, 329 patients were included in this analysis, with disease progression in 63 patients. Concerning the primary study aim, progression status predicted MID of global HRQoL status in addition to the other covariates. The adjusted odds ratio for the effect of progression status on MID was 2.22 (95% CI: 1.04 - 4.73). Comparisons of mean differences of QoL domains/scales yielded no differences. Conclusions We provide evidence that disease progression in patients with metastatic breast cancer in a real-world registry has a significant negative impact on HRQoL as measured by MID of HRQoL. This study emphasizes the relevance of avoiding progression and prolonging PFS to maintain QoL. [ABSTRACT FROM AUTHOR]

Published
2018
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9. Identification and Functional Testing of ERCC2 Mutations in a Multi-national Cohort of Patients with Familial Breast- and Ovarian Cancer.

Author

Rump, Andreas, Benet-Pages, Anna, Schubert, Steffen, Kuhlmann, Jan Dominik, Janavičius, Ramūnas, Macháčková, Eva, Foretová, Lenka, Kleibl, Zdenek, Lhota, Filip, Zemankova, Petra, Betcheva-Krajcir, Elitza, Mackenroth, Luisa, Hackmann, Karl, Lehmann, Janin, Nissen, Anke, DiDonato, Nataliya, Opitz, Romy, Thiele, Holger, Kast, Karin, and Wimberger, Pauline

Subjects
OVARIAN cancer, BREAST cancer, CANCER genetics, GENETIC polymorphisms, MAGNETIC domain, FERROMAGNETIC materials
Abstract

The increasing application of gene panels for familial cancer susceptibility disorders will probably lead to an increased proposal of susceptibility gene candidates. Using ERCC2 DNA repair gene as an example, we show that proof of a possible role in cancer susceptibility requires a detailed dissection and characterization of the underlying mutations for genes with diverse cellular functions (in this case mainly DNA repair and basic cellular transcription). In case of ERCC2, panel sequencing of 1345 index cases from 587 German, 405 Lithuanian and 353 Czech families with breast and ovarian cancer (BC/OC) predisposition revealed 25 mutations (3 frameshift, 2 splice-affecting, 20 missense), all absent or very rare in the ExAC database. While 16 mutations were unique, 9 mutations showed up repeatedly with population-specific appearance. Ten out of eleven mutations that were tested exemplarily in cell-based functional assays exert diminished excision repair efficiency and/or decreased transcriptional activation capability. In order to provide evidence for BC/OC predisposition, we performed familial segregation analyses and screened ethnically matching controls. However, unlike the recently published RECQL example, none of our recurrent ERCC2 mutations showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. Interestingly, we detected that some deleterious founder mutations had an unexpectedly high frequency of > 1% in the corresponding populations, suggesting that either homozygous carriers are not clinically recognized or homozygosity for these mutations is embryonically lethal. In conclusion, we provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of “bonafide” breast cancer susceptibility genes. [ABSTRACT FROM AUTHOR]

Published
2016
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10. Evaluation of prognostic factors following flow-cytometric DNA analysis after cytokeratin labelling: I. Breast cancer.

Author

Wimberger, Pauline, Hillemanns, Peter, Kapsner, Thomas, Hepp, Hermann, and Kimmig, Rainer

Subjects
*BREAST cancer, *CANCER prognosis
Abstract

In gynecologic oncology valid prognostic factors are necessary to estimate the course of disease and to define biologically similar subgroups for analysis of therapeutic efficacy. The presented study is a prospective study concerning prognostic significance of DNA ploidy and S-phase fraction in breast cancer following enrichment of rumor cells by cytokeratin labelling. Epithelial cells were labeled by FITC-conjugated cytokeratin antibody (CK 5, 6, 8, and CK 17) prior to flow cytometric cell cycle analysis in 327 fresh specimens of primary breast cancer. Univariate analysis in breast cancer detected the prognostic significance of DNA-ploidy, S-phase fraction and CV (coefficient of variation) of G[sub 0]G[sub 1] -peak of tumor cells for clinical outcome, especially for nodal-negative patients. Multivariate analysis could not confirm prognostic evidence of DNA-ploidy and S-phase fraction. In conclusion, in breast cancer no clinical significance for determination of DNA-parameters was found. [ABSTRACT FROM AUTHOR]

Published
2002
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11. Flow cytometric DNA analysis using cytokeratin labeling for identification of tumor cells in carcinomas of the breast and the female genital tract.

Author

Kimmig, Rainer, Wimberger, Pauline, Kapsner, Thomas, and Hillemanns, Peter

Subjects
*FLOW cytometry, *TUMORS, *BREAST cancer
Abstract

Flow cytometric assessment of DNA-ploidy and S-phase fraction in malignant tumors is compromised by the heterogeneity of cell subpopulations derived from the malignant and surrounding connective tissue, e.g., tumor, stromal and inflammatory cells. To evaluate the effect on quality of DNA cell cycle analysis and determination of DNA ploidy, cytokeratin labeling of epithelial cells was used for tumor cell enrichment in breast, ovarian, cervical and endometrial cancer prior to DNA analysis. In a prospective study, tumor cell subpopulations of 620 malignant tumors were labeled by a FITC-conjugated cytokeratin antibody (CK 5, 6, CK18 and CK 5, 6, 8 and CK 17, respectively) prior to flow cytometric cell cycle analysis. Compared to total cell analysis, detection rate of DNA-aneuploid tumors following cytokeratin labeling was increased from 62% to 76.5% in breast cancer, from 68% to 77% in ovarian cancer, from 60% to 80% in cervical cancer and from 30% to 53% in endometrial cancer. Predominantly in DNA-diploid tumors, a significantly improved detection of S-phase fraction of the tumor cells was shown due to the elimination of contaminating nonproliferating “normal cells”. S-phase fraction following tumor cell enrichment was increased by 10% (mean) following cytokeratin staining in ovarian and endometrial cancer, by 30% in breast cancer and even by 70% in cervical cancer compared to total cell analysis. Thus, diagnostic accuracy of DNA-analysis was enhanced by cytokeratin labeling of tumor cells for all tumor entities investigated. [ABSTRACT FROM AUTHOR]

Published
2001
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12. Association of caspase 8 polymorphisms -652 6N InsDel and Asp302His with progression-free survival and tumor infiltrating lymphocytes in early breast cancer.

Author

Kuhlmann, Jan Dominik, Bachmann, Hagen Sjard, Link, Theresa, Wimberger, Pauline, Kröber, Eric, Thomssen, Christoph, Mallé, Brahima, Bethmann, Daniel, Vetter, Martina, and Kantelhardt, Eva Johanna

Subjects
CASPASES, PROGRESSION-free survival, LYMPHOCYTES, BREAST cancer, HOMOZYGOSITY, PYROSEQUENCING
Abstract

The caspase 8 variants CASP8 -652 6N InsDel and Asp302His have previously been identified to promote survival of T-lymphocytes and to indicate reduced breast cancer susceptibility. Besides some preliminary findings, prognostic relevance of these polymorphisms in patients with existing breast cancer has not been investigated. Considering an immunomodulatory role of these polymorphisms, we genotyped 785 early breast cancer patients and correlated caspase 8 variants with disease-free survival (DFS) and the presence of tumor infiltrating lymphocytes (TILs). Early breast cancer specimens were collected as part of the multicenter prospective PiA study. Genotyping was performed by pyrosequencing, TILs status was assessed using hematoxylin & eosin staining. The CASP8 -652Del variant was significantly associated with improved DFS in an allele-dose dependent manner (p = 0.027). Homozygosity for the -652Del variant was an independent predictor for improved DFS (HR = 0.36; 95% CI = 0.174–0.726; p = 0.005). In patients with the 302HisHis genotype, there was no event of recurrence during observation time. Combined analysis of diplotypes revealed an influence of both polymorphisms on DFS (p = 0.029). Interestingly, patients with the 302HisHis variant among the unstratified patient cohort (and among the luminal-like subtype, by trend) had tumors with lower lymphocyte infiltration (p = 0.025). We propose a prognostically favorable role of the -652Del and the 302His variant in primary breast cancer and suggest for the first time an association between polymorphisms in apoptosis-related genes and the immunophenotype in breast cancer. Our findings encourage further investigation of caspase 8 polymorphisms as biomarkers for prognostic and immunotherapeutic considerations. [ABSTRACT FROM AUTHOR]

Published
2019
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13. Plasma levels of Semaphorin 4D are decreased by adjuvant tamoxifen but not aromatase inhibitor therapy in breast cancer patients.

Author

Göbel, Andy, Kuhlmann, Jan D., Link, Theresa, Wimberger, Pauline, Link-Rachner, Cornelia, Thiele, Stefanie, Dell'Endice, Stefania, Furesi, Giulia, Breining, Dorit, Rauner, Martina, Hofbauer, Lorenz C., and Rachner, Tilman D.

Abstract

Semaphorin 4D (Sema4D) is a glycoprotein that inhibits bone formation and has been associated with cancer progression and the occurrence of bone metastases. Recently, Sema4D expression has been linked to estrogen signaling in breast cancer. Endocrine therapies like tamoxifen and aromatase inhibitors (AI) are a standard therapeutic approach in hormone receptor positive breast cancers. Tamoxifen exerts ER-agonistic effects on bone, whereas AI negatively affect bone health by increasing resorption and fracture risk. The effect of endocrine therapies on circulating Sema4D levels in breast cancer patients has not been investigated yet. We measured circulating Sema4D plasma levels at primary diagnosis and in a follow-up sample 12 months after surgery in a cohort of 46 pre- and postmenopausal women with primary estrogen receptor positive breast cancer receiving adjuvant tamoxifen or AI. The mean baseline levels ± SD for Sema4D were 441.6 ± 143.4 pmol/l. No significant differences in total plasma Sema4D were observed when stratifying the patients according to age, menopausal status, tumor subtype, nodal and hormone receptor status, or tumor size. However, Sema4D levels were significantly reduced by 28% (p <0.001) in tamoxifen treated patients 12 months after surgery, whereas no alteration was observed in patients treated with AI. This finding potentially represents an additional mechanism of the bone-protective properties of tamoxifen and further emphasizes a link between Sema4D and estrogen receptor signaling. [ABSTRACT FROM AUTHOR]

Published
2019
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14. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials.

Author

Denkert, Carsten, Seither, Fenja, Schneeweiss, Andreas, Link, Theresa, Blohmer, Jens-Uwe, Just, Marianne, Wimberger, Pauline, Forberger, Almuth, Tesch, Hans, Jackisch, Christian, Schmatloch, Sabine, Reinisch, Mattea, Solomayer, Erich F, Schmitt, Wolfgang D, Hanusch, Claus, Fasching, Peter A, Lübbe, Kristina, Solbach, Christine, Huober, Jens, and Rhiem, Kerstin

Subjects
*BREAST cancer, *OVERALL survival, *LOG-rank test, *HORMONE receptor positive breast cancer, *CLINICAL trials, *SURVIVAL analysis (Biometry)
Abstract

Background: The development of anti-HER2 antibody-drug conjugates opens new therapeutic options for patients with breast cancer, including patients with low expression of HER2. To characterise this new breast cancer subtype, we have compared the clinical and molecular characteristics of HER2-low-positive and HER2-zero breast cancer, including response to neoadjuvant chemotherapy and prognosis.Methods: In this pooled analysis of individual patient data, we evaluated a cohort of 2310 patients with HER2-non-amplified primary breast cancer that were treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials (GeparSepto, NCT01583426; GeparOcto, NCT02125344; GeparX, NCT02682693; Gain-2 neoadjuvant, NCT01690702) between July 30, 2012, and March 20, 2019. Central HER2 testing was done prospectively before random assignment of participants in all trials. HER2-low-positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology/College of American Pathologists guidelines. Disease-free survival and overall survival data were available for 1694 patients (from all trials except GeparX) with a median follow-up of 46·6 months (IQR 35·0-52·3). Bivariable and multivariable logistic regression models and Cox-proportional hazards models were performed based on a predefined statistical analysis plan for analysis of the endpoints pathological complete response, disease-free survival, and overall survival.Findings: A total of 1098 (47·5%) of 2310 tumours were HER2-low-positive and 1212 (52·5%) were HER2-zero. 703 (64·0%) of 1098 patients with HER2-low-positive tumours were hormone receptor positive, compared with 445 (36·7%) of 1212 patients with HER2-zero tumours (p<0.0001). HER2-low-positive tumours had a significantly lower pathological complete response rate than HER2-zero tumours (321 [29·2%] of 1098 vs 473 [39·0%] of 1212, p=0·0002). Pathological complete response was also significantly lower in HER2-low-positive tumours versus HER2-zero tumours in the hormone receptor-positive subgroup (123 [17·5%] of 703 vs 105 [23·6%] of 445, p=0·024), but not in the hormone receptor-negative subgroup (198 [50·1%] of 395 vs 368 [48·0%] of 767, p=0·21). Patients with HER2-low-positive tumours had significantly longer survival than did patients with HER2-zero tumours (3-year disease-free survival: 83·4% [95% CI 80·5-85·9] vs 76·1% [72·9-79·0]; stratified log-rank test p=0·0084; 3-year overall survival: 91·6% [84·9-93·4] vs 85·8% [83·0-88·1]; stratified log-rank test p=0·0016). Survival differences were also seen in patients with hormone receptor-negative tumours (3-year disease-free survival: 84·5% [95% CI 79·5-88·3] vs 74·4% [70·2-78.0]; stratified log-rank test p=0·0076; 3-year overall survival: 90·2% [86·0-93·2] vs 84·3% [80·7-87·3], stratified log-rank test p=0·016), but not in patients with hormone receptor-positive tumours (3-year disease-free survival 82·8% [79·1-85·9] vs 79·3% [73·9-83·7]; stratified log-rank test p=0·39; 3-year overall survival 92·3% [89·6-94·4] vs 88·4% [83·8-91·8]; stratified log-rank test p=0·13).Interpretation: Our results show that HER2-low-positive tumours can be identified as new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours. HER2-low-positive tumours have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumours. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies.Funding: German Cancer Aid (Deutsche Krebshilfe). [ABSTRACT FROM AUTHOR]

Published
2021
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