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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

Aim: To report on the management strategies in patients with cancer of unknown primary (CUP) in middle-income countries. Methods: We conceived a survey of 20 items concerning the management of patients with CUP in daily clinical practice. Only participants from lower- and higher-middle-income countries, as per the World Bank Classification, were eligible for this study. Results: The indications for the first-line treatment did not differ between the two economic regions, whereas those for second-line treatment were more prevalent in higher-middle-income countries. The use of targeted therapy based on immunohistochemistry alone was higher in lower-middle-income countries, although the access to CUP classifiers was similar between the two regions. Conclusions: Proper recommendations must ensure that the economic burden is minimized and that other benefits outweigh the limited survival benefit achieved in patients with CUP.

BACKGROUND Female patients undergoing anticancer treatment are at elevated risk of adverse ovarian outcomes including infertility and premature ovarian insufficiency (POI), which is associated with short- and long-term health risks. Anti-Müllerian hormone (AMH) is a key biomarker of ovarian reserve, but its role prior to and after cancer treatment is less well understood. OBJECTIVE AND RATIONALE To conduct a systematic review evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment, which has become a pressing clinical issue in reproductive medicine. There are a large number of observational studies, but differences in patient groups, cancer diagnoses and study design make this a confusing field that will benefit from a thorough and robust review. SEARCH METHODS A systematic literature search for AMH in women with cancer was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 April 2021. Bias review was conducted using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol along with qualitative assessment of quality. Exploratory subgroups were established based on age, cancer type and length of follow-up. OUTCOMES Ninety-two publications (N = 9183 patients) were included in this analysis after quality and bias review. Reduced/undetectable AMH was consistently identified in 69/75 studies (92%) following chemotherapy or radiotherapy, with reductions ranging from 42% to concentrations below the limit of detection, and many reporting mean or median declines of ≥90%. Where longitudinal data were analysed (42 studies), a majority (33/42 (79%)) of studies reported at least partial recovery of AMH at follow-up, however, effect estimates were highly variable, reflecting that AMH levels were strongly impacted by anticancer treatment (i.e. the chemotherapy regimen used and the number of treatment cycles need), with recovery and its degree determined by treatment regimen, age and pre-treatment AMH level. In 16/31 (52%) publications, oligo/amenorrhoea was associated with lower post-treatment AMH consistent with impending POI, although menstruation and/or pregnancy were reported in patients with low or undetectable AMH. Long-term (>5 years) follow-up of paediatric patients following cancer treatment also found significantly lower AMH compared with control groups in 14/20 (70%) of studies, with very variable effect sizes from complete loss of AMH to full recovery depending on treatment exposure, as in adult patients. WIDER IMPLICATIONS AMH can be used to identify the damaging effect of cancer treatments on ovarian function. This can be applied to individual women, including pre-pubertal and adolescent girls, as well as comparing different treatment regimens, ages and pre-treatment AMH levels in populations of women. While there was evidence for its value in the diagnosis of POI after cancer treatment, further studies across a range of diagnoses/treatment regimens and patient ages are required to clarify this, and to quantify its predictive value. A major limitation for the use of AMH clinically is the very limited data relating post-treatment AMH levels to fertility, duration of reproductive lifespan or time to POI; analysis of these clinically relevant outcomes will be important in further research.

Different chemotherapy regimens may contribute differently to the development of Premature Ovarian Failure (POF) in women of reproductive age with breast cancer. Here we evaluated how two different chemotherapy regimens, CAF (tegafur + pirarubicin + ifosfamide) and DTC (docetaxel + pirarubicin + ifosfamide), affect the development of POF.We enrolled 164 women of reproductive age with breast cancer (mean ± SD age of 34.56 ± 9.48 years). The patients were divided into two groups, which were respectively treated with CAF (n = 89) or DTC (n = 75) chemotherapy regimen. Both study groups were comparable in all analyzed characteristics at baseline. Patients were treated with respective chemotherapy regimen for 6 months and followed up for over 12 months after completion of chemotherapy. Study outcomes were occurrence rates of POF, menstrual status and recovery after completion of chemotherapy, and serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and oestradiol (E2).At 6 months after completion of chemotherapy, POF incidence rates were significantly lower in the CAF group. Furthermore, the proportion of patients with eumenorrhea, menstrual disorders or chemotherapy-induced amenorrhea in this study group was also significantly different from the DTC group. Similarly, adverse changes of serum levels of FSH, LH and E2 were less pronounced in the CAF group.Both tested chemotherapy regimens can cause POF; however, adverse effects of DCT chemotherapy regimen on ovarian function are more pronounced than those by CAF chemotherapy regimen.

Cancer in pregnancy is a rare disease with breast cancer, cervical cancer, melanoma and Hodgkin's disease to be the most commonly diagnosed malignancies during gestation. Cancer of unknown primary (CUP) is a well-recognized clinical disorder where the primary site can not be identified after a standard diagnostic approach. CUP in pregnancy has rarely been described.We searched MEDLINE and contacted cancer Centers in Europe, United States and Australia where patients with CUP or pregnant patients with cancer were diagnosed and treated.Since 1976 we identified 18 pregnant women with CUP in a median gestational age of 34 weeks. Most of these patients were diagnosed with poorly-differentiated histology, had poor response to systemic treatment and a median maternal survival of 8 months. Seventy-two percent of mothers have died, while 80% of the newborns were alive and healthy. Almost one fourth of placentas examined showed metastatic disease.CUP during pregnancy is a very rare coexistence, usually has an aggressive disease with poor response to chemotherapy and a dismal prognosis. Both obstetricians and oncologists should be aware of this rare condition.

Background Epidemiological evidence indicates a clear relationship between pregnancy and breast cancer (BC) risk. However, little is known regarding the impact of pregnancy on BC biology. DNA copy number aberrations (CNAs) play an important role in breast carcinogenesis. BC during pregnancy is a rare disease, however it can be used as a model to study the impact of pregnancy on BC biology. Methods We retrospectively included 54 pregnant and 113 non-pregnant BC patients matched for age and stage with complete clinic-pathological, gene expression and 5-year follow-up data. CNAs were assessed using Affymetrix OncoScan FFPE arrays. First, we filtered genes whose expression was driven by CNAs. Then, we identified genes that were differentially affected by pregnancy both at the CNA and the gene expression level. Results After quality control, CNA profiles were obtained for 38 pregnant and 87 non-pregnant BC patients. There were no significant differences in classical clinic-pathological features (pT, pN, grade, PAM50). We selected 1981 genes whose expression was correlated with CNAs (ρ ≥ 0.4). Among these, 77 genes were altered at the expression level (p ≤ 0.01) between pregnant and control patients, whereas 171 genes were altered at the CNA level (p ≤ 0.05). Twenty-eight genes were concomitantly altered at the expression and CNA levels which was significantly higher than expected (p = 0.021, permutation test). These genes were mapped on three different chromosomes. Genes located on chr7q and chr11q were associated with copy number gains and were up-regulated in pregnant patients whereas genes located on chr22q were associated with copy number loss in control patients. Of interest we identified 6 putative oncogenes (CDK6, ESRRA, S6K2, LIMK2, MKL1) that were up-regulated in pregnant patients. A ‘pregnancy-associated breast cancer signature’ was computed from the expression of the 28 genes. There was a negative relationship between the signature and the expression of ESR1 and PGR genes. This signature was significantly more correlated with the proliferation-associated AURKA gene in pregnant patients as compared to control (ρ = 0.73 vs ρ = 0.24, p = 0.001). Conclusions In this study, we were able to identify several genomic alterations associated with pregnancy that could help elucidate the impact of pregnancy on BC risk. Moreover, by combining CNAs with gene expression, we were able to identify genes that could be responsible for the poorer prognosis seen in pregnancy-associated breast cancer and could be potential drivers of this rare disease. Citation Format: Bastien Nguyen, David Venet, Françoise Rothé, Christine Desmedt, Samira Majjaj, Giancarlo Pruneri, David Brown, Fedro Peccatori, Hatem A. Azim, Christos Sotiriou. Interrogating the impact of pregnancy on breast cancer biology using DNA copy number profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1452. doi:10.1158/1538-7445.AM2017-1452