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Background Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti-Müllerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21). Methods We identified 170 premenopausal patients, age ≤ 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA). Results Median age was 36 years (21–40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1–11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1–0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1–3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients. Conclusions In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Obesity and the presence of circulating tumor cells (CTCs) before and/or after chemotherapy are associated with poor outcome in breast cancer (BC) patients. The activation of oncogenic pathways in fatty tissue leads to cell proliferation, suggesting a possible link between obesity and CTCs., Materials and Methods: In the phase III SUCCESS A trial, 3754 patients with early BC were randomized to 3 cycles of fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine. Data of 1088 patients with CTC assessments (CellSearch-System; Menarini Silicon Biosystems, Italy) and body mass index (BMI) measurements both before and after chemotherapy were available. Patients were classified according to the WHO's international definitions as underweight, normal weight, overweight, or obese, and according to their weight-change during chemotherapy into a weight-loss group (> 5% decrease), stable-weight group (≤ 5% weight-change) or weight-gain group (>5% increase). Associations between CTC positivity and, BMI or weight-change group were analyzed using frequency-table methods., Results: At study entry, 47.4% patients were underweight or normal weight, 33.6% were overweight and 18.9% were obese. Before and after chemotherapy, CTCs were detected in 20.1% and 22.6% of patients, respectively. There was no association between CTC positivity and BMI before (P = 0.104) or after (P = 0.051) chemotherapy. Furthermore, there was no association between weight-change group and CTC status before/after chemotherapy (P = 0.332)., Conclusions: According to our analysis, the risk factors obesity and prevalence of CTCs are not associated and may represent independent prognostic factors., Competing Interests: Disclosure TWP: Personal fees from Lilly and Novartis. FS: Grants from AstraZeneca, Roche and Karyopharm. Personal fees from Roche, Pfizer, Novartis, AstraZeneca, GSK, MSD, Clovis and Eisai. TF: Personal fees from Medconcept, Onkowissen. KP: Grants from: EU/IMI CANCER-ID EFPIA, Personal fees from: BMS, Agena, Menarini, Novartis, Sanofi, Illumina, Abcam, MSD, Boehringer Ingelheim, Eppendorf and Hummingbird. AS: Grants from Celgene, Roche and AbbVie. Personal fees from Celgene, Roche, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Seagen, Gilead, GSK, Bayer, Amgen and Pierre Fabre. HT: Personal fees from Novartis, Roche, GSK, Seagan, Pfizer, Lilly, Astra Zeneca, Daiichi, Exact Science, Vifor and Seagan. Shares/stocks from CHOP GmbH, VISION MED GmbH, Care and Coach GmbH, Onco Medical Consult GmbH. VA-F: Honoraria from Novartis. PF: Grants from Pfizer, Cepheid and Biontech. Personal fees from Novartis Daiichi-Sankyo, Pfizer Astra Zeneca, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, SeaGen, Roche, Agendia, Sanofi Aventis, Gilead, Mylan and Menarini., WJ: honoraria from Sanofi-Aventis, Novartis and Pfizer. BR: honoraria from AstraZeneca, Chugai, Lilly, Novartis, Sanofi-Aventis, and Jannssen-Cilag. All other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

The prognostic relevance of circulating tumor cells (CTCs) in breast cancer is well established. However, little is known about the association of CTCs and site of first metastasis. In the SUCCESS A trial, 373 out of 3754 randomized high-risk breast cancer patients developed metastatic disease. CTC status was assessed by the FDA-approved CellSearch ® -System (Menarini Silicon Biosystems, Bologna, Italy) in 206 of these patients before chemotherapy and additionally in 159 patients after chemotherapy. CTCs were detected in 70 (34.0%) of 206 patients before (median 2 CTCs, 1-827) and in 44 (27.7%) of 159 patients after chemotherapy (median 1 CTC, 1-124); 16 (10.1%) of 159 patients were CTC-positive at both timepoints. The site of first distant disease was bone-only, visceral-only, and other-site-only in 44 (21.4%), 60 (29.1%), and 74 (35.9%) patients, respectively, while 28 (13.6%) patients had multiple sites of first metastatic disease. Patients with CTCs at both timepoints more often showed bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs before and/or after chemotherapy ( p = 0.027). In conclusion, the presence of CTCs before and after chemotherapy is associated with multiple-site or bone-only first-distant disease and may trigger intensified follow-up and perhaps further treatment.

Purpose: To study trends regarding the use of contraceptive methods and digital health modalities and to identify target groups of natural family planning (NFP)., Material and Methods: Using an online questionnaire specifically developed for this study in German (utilizing the online tool at 'www.surveymonkey.com'), we analysed the attitude towards NFP -methods and -apps, the need for contraceptive effectiveness in general, the perceived contraceptive effectiveness of NFP methods, and differences between NFP users and non-NFP users among 779 sexually active German-speaking women of fertile age (18-50 years) from November 2019 to October 2020., Results and Conclusions: Participants used NFP more frequently than they did five years ago. Women aged 30 years and older, with higher levels of education, who are living with a partner and have children, seem to be the target group for NFP methods. Concerning the wish for contraceptive effectiveness we found significant ( p  < .001) differences between NFP and non-NFP users. Furthermore, an increasing number of women wants to use NFP-methods and -apps for contraception; thus, non-hormonal contraceptive options should be offered. The majority of current NFP users stated that the handling and effectiveness of NFP have been improved by digitalisation.

Evidence suggests that the DNA end-binding protein p53-binding protein 1 (53BP1) is down-regulated in subsets of breast cancer. Circulating tumor cells (CTCs) provide accessible "biopsy material" to track cell traits and functions and their alterations during treatment. Here, we prospectively monitored the 53BP1 status in CTCs from 67 metastatic breast cancer (MBC) patients with HER2- CTCs and known hormone receptor (HR) status of the primary tumor and/or metastases before, during, and at the end of chemotherapeutic treatment with Eribulin. Nuclear 53BP1 staining and genomic integrity were evaluated by immunocytochemical and whole-genome-amplification-based polymerase chain reaction (PCR) analysis, respectively. Comparative analysis of CTCs from patients with triple-negative and HR+ tumors revealed elevated 53BP1 levels in CTCs from patients with HR+ metastases, particularly following chemotherapeutic treatment. Differences in nuclear 53BP1 signals did not correlate with genomic integrity in CTCs at baseline or with nuclear γH2AX signals in MBC cell lines, indicating that 53BP1 detected features beyond DNA damage. Kaplan-Meier analysis revealed an increasing association between nuclear 53BP1-positivity and progression-free survival (PFS) during chemotherapy until the final visit. Our data suggest that 53BP1 detection in CTCs could be a useful marker to capture dynamic changes of chemotherapeutic responsiveness in triple-negative and HR+ MBC.

Mutations in the ligand-binding domain (LBD) of the ESR1 gene result in resistance to estrogen deprivation therapy (EDT) in breast cancer. Their detection might enable optimization of therapy strategies. However, the predictive utility of the primary tumor (PT) is limited, and obtaining serial biopsies of metastatic lesions is challenging. To underline their application as a liquid biopsy, single circulating tumor cells (CTCs) were analyzed with a next-generation sequencing approach for the ESR1 coding region. CTCs from 46 metastatic luminal breast cancer patients were enriched using CellSearch system and isolated by micromanipulation. Their genomic DNA was amplified and the ESR1 gene was sequenced. Furthermore, tissue samples from corresponding PTs and/or metastatic lesions were investigated. ESR1 mutations were detected in 12 patients-exclusively in patients treated with EDT (P = 0.048). In seven cases mutations were located in the hotspot regions in the LBD. Six novel mutations were identified. ESR1 mutations were absent in PT tissue samples and were detected only in metastases obtained after CTC characterization. Single-cell CTC analysis for ESR1 mutations could be of clinical value to identify patients who progress under EDT and therefore benefit from an early switch to an alternative endocrine therapy or other treatment regimens. Furthermore, our data indicate that mutations outside the LBD's hotspot regions might also contribute to resistance to EDT., (Copyright © 2020 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic relevance of circulating tumor cells (CTCs) at the time of primary diagnosis has been well established. However, little information is available regarding their prognostic relevance to follow-up care., Methods: The multicenter, open-label, phase III SUCCESS A trial compared two adjuvant chemotherapy regimens followed by 2 vs 5 years of zoledronate for early-stage, high-risk breast cancer patients. The presence of CTCs was assessed before and 2 years after chemotherapy using the FDA-approved CellSearch System. Overall survival (OS) and disease-free survival (DFS) were analyzed using univariate log-rank tests and multivariable Cox regressions. OS and DFS were measured starting from an assessment of CTCs 2 years after the completion of chemotherapy. All statistical tests were two-sided., Results: The sample included 1087 patients who participated in the translational research program of the SUCCESS A trial and for whom sufficient translational data were available regarding CTC status at baseline and at the 2-year follow-up visit. Two years after chemotherapy, 198 (18.2%) patients were CTC-positive. The median follow-up after this timepoint was 37 months. Cox regressions that included CTC status at baseline revealed that CTC status 2 years after chemotherapy had statistically significant and independent prognostic relevance for OS (hazard ratio [HR] = 3.91, 95% confidence interval [CI] = 2.04 to 7.52, P < .001) and DFS (HR = 2.31, 95% CI = 1.50 to 3.55, P < .001)., Conclusion: The presence of CTCs 2 years after chemotherapy was associated with decreased OS and DFS. Based on these results, active individualized surveillance strategies for breast cancer survivors based on biomarkers should be reconsidered., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The presence of high expressing epithelial cell adhesion molecule (EpCAM high ) circulating tumor cells (CTC) enumerated by CellSearch ® in blood of cancer patients is strongly associated with poor prognosis. This raises the question about the presence and relation with clinical outcome of low EpCAM expressing CTC (EpCAM low CTC). In the EU-FP7 CTC-Trap program, we investigated the presence of EpCAM high and EpCAM low CTC using CellSearch, followed by microfiltration of the EpCAM high CTC depleted blood. Blood samples of 108 castration-resistant prostate cancer patients and 22 metastatic breast cancer patients were processed at six participating sites, using protocols and tools developed in the CTC-Trap program. Of the prostate cancer patients, 53% had ≥5 EpCAM high CTC and 28% had ≥5 EpCAM low CTC. For breast cancer patients, 32% had ≥5 EpCAM high CTC and 36% had ≥5 EpCAM low CTC. 70% of prostate cancer patients and 64% of breast cancer patients had in total ≥5 EpCAM high and/or EpCAM low CTC, increasing the number of patients in whom CTC are detected. Castration-resistant prostate cancer patients with ≥5 EpCAM high CTC had shorter overall survival versus those with <5 EpCAM high CTC ( p = 0.000). However, presence of EpCAM low CTC had no relation with overall survival. This emphasizes the importance to demonstrate the relation with clinical outcome when presence of CTC identified with different technologies are reported, as different CTC subpopulations can have different relations with clinical outcome., Competing Interests: CONFLICTS OF INTEREST None of the authors have conflicts of interest to declare.

Background: microRNAs (miRNAs) are considered promising cancer biomarkers, showing high reliability, sensitivity and stability. Our study aimed to identify associations between whole blood miRNA profiles, presence of circulating tumor cells (CTCs) and clinical outcome in post-operative early breast cancer patients (EBC) to assess the utility of miRNAs as prognostic markers in this setting., Method: A total of 48 post-operative patients, recruited in frame of the SUCCESS A trial, were included in this retrospective study and tested with a panel of 8 miRNAs (miR-10b, -19a, - 21, - 22, -20a, - 127, - 155, -200b). Additional 17 female healthy donors with no previous history of cancer were included in the study as negative controls. Blood samples were collected at different time points (pre-adjuvant therapy, post-adjuvant therapy, 2 years follow up), total RNA was extracted and the relative concentration of each miRNA was measured by quantitative PCR and compared in patients stratified on blood collection time or CTC detection. Furthermore, we compared miRNA profiles of patients, for each time point separately, and healthy donors. CTCs were visualized and quantified with immunocytochemistry analysis. Data were analyzed using non-parametric statistical tests., Results: In our experimental system, miR-19a, miR-22 and miR-127 showed the most promising results, differentiating patients at different time points and from healthy controls, while miR-20a, miR-21 and miR-200b did not show any difference among the different groups. miR-10b and miR-155 were never detectable in our experimental system. With respect to patients' clinical characteristics, we found a significant correlation between miR-200b and lymph node status and between miR-20a and tumor type. Furthermore, miR-127 correlated with the presence of CTCs. Finally, we found a borderline significance between Progression Free Survival and miR-19a levels., Conclusions: This pilot study suggests that profiling whole blood miRNAs could help to better stratify post-operative EBC patients without any sign of metastasis to prevent later relapse or metastatic events.

Background: Optimal choice and sequence of endocrine treatment following adjuvant chemotherapy in postmenopausal early breast cancer patients are still under discussion and treatment stratification factors are missing., Patients and Methods: Postmenopausal women with HER2-negative, hormone receptor-positive tumors and persisting circulating tumor cells (CTCs; assessed using the FDA-approved CellSearch® System, Janssen Diagnostics, LLC) after chemotherapy were randomized to 2 years of tamoxifen followed by 3 years of exemestane (tamoxifen-exemestane group, n = 54) or 5 years of exemestane (exemestane-only group, n = 54). CTCs were again assessed after the first 2 years of endocrine treatment. In addition, safety data were compared between the 2 groups., Results: The 2 groups were well-balanced with regard to baseline characteristics. The CTC clearance rate after 2 years was 89% in the exemestane-only group and 97% in the tamoxifen-exemestane group (exact Fisher test, p = 0.36). The safety profile showed good tolerability with few grade 3 or 4 adverse events in both groups., Conclusion: The similar CTC clearance rate after 2 years of endocrine therapy with exemestane or tamoxifen, and the safety profiles obtained may indicate comparable efficacy and tolerability of both endocrine treatment regimens. However, these results have to be confirmed by final survival and safety analysis., (© 2018 S. Karger GmbH, Freiburg.)

Dissemination of tumour cells and the development of solid metastases occurs via blood vessels and lymphatics. Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) can be detected in venous blood in patients with early and metastatic breast cancer, and their prognostic relevance has been demonstrated on numerous occasions. Repeated testing for CTCs and ctDNA, or regular so-called "liquid biopsy", can be performed easily at any stage during the course of disease. Additional molecular analysis allows definition of tumour characteristics and heterogeneity that may be associated with treatment resistance. This in turn makes personalised, targeted treatments possible that may achieve both improved overall survival and quality of life.