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Purpose: We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor-positive breast cancer (BC) desiring future pregnancy., Patients and Methods: POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months., Results: Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5)., Conclusion: In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

Background: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking., Methods: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial., Results: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort., Conclusions: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy., Methods: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration., Findings: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %)., Interpretation: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world., Competing Interests: Declaration of competing interest Ann H. Partridge reports no conflicts related to this trial. Samuel M. Niman reports no conflicts related to this trial. Monica Ruggeri reports no conflicts related to this trial. Fedro A. Peccatori receives honoraria from Roche Diagnostic and Ipsen. Hatem A Azim Jr receives honoraria from Novartis, serves on the Roche Adviosry Board and is employed with Innate Pharma. Marco Colleoni reports no conflicts related to this trial. Cristina Saura receives consulting or advisory fees from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann-La Roche Ltd, Genomic Health, Merck, Sharp and Dhome España SA, Novartis, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma biotechnology, Synthon, Seattle Genetics, and Sanofi Aventis. Chikako Shimizu receives honoraria from Pfizer, Chugai, and Novartis and has a research grant from Eli-Lilly; none of these are trial related. Anna Barbro Sætersdal reports no conflicts related to this trial. Judith R Kroep reports no trial related conflicts. Audrey Mailliez reports no trial related conflicts. Ellen Warner reports no conflicts related to this trial. Virginia F. Borges receives consulting fees from SeaGen. Frédéric Amant receives honoraria from AstraZeneca and PharmaMar. Andrea Gombos is on the advisory boards of Lilly and Daiichi Sankyo, receives a travel grant from Pfizer; none of these are related to this trial. Akemi Kataoka reports no conflicts related to this trial. Christine Rousset-Jablonski receives honoraria or advisory fees from Amgen, Astra Zeneca, Eli Lilly, Krka, Merck, Novartis, Pfizer, or Roche; none of these are trial related. Simona Borstnar serves on the advisory boards for Mylan Medical, Roche, and BMS; none of these are trial related. Junko Takei reports no conflicts related to this trial. Jeong Eon Lee reports no conflicts related to this trial. Janice M. Walshe receives honoraria from Novartis; consulting or advisory fees from Pierre Fabre, Pfizer, or Roche. Manuel Ruíz Borrego receives spekear grants from Pifzer, Novartis, Puma, AstraZeneca, and Roche; and receives advisory honoraria from Pfizer, Novartis, and Puma. Halle C.F. Moore receives research funding (to her Institution) from AstraZeneca, Roche/Genentech, Daiichi-Sankyo, and Sermonix. Christobel Saunders receives honoraria from Roche, Pfizer and GenesisCare. Fatima Cardoso serves an advisory role for Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seattle Genetics, and Teva; none of these are trial related. Snezana Susnjar receives honoraria or advisory fees from Roche, Pfizer, Novartis, AstraZeneca, and Amicus; none of these are trial related. Vesna Bjelic-Radisic receives honoraria from Novartis, AstraZeneca, and Roche; receives consulting or advisory fees from Pfizer or Lilly; none of these are trial related conflicts. Karen L. Smith reports that her spouse has stock in Abbott Laboratories and Abbvie and that she receives research funding (to her Institution) from Pfizer; one of these are trial-related. Martine Piccart receives honoraria from AstraZeneca, Camel-IDS, Debiopharm, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Seattle Genetics, and Immutep; receives research grants (to her Institution) from AstraZeneca, Immunomedics, Lilly, Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, and Synthon and is a scientific board member for Oncolytics. Larissa A. Korde reports no conflicts related to this trial. Richard D. Gelber receives research funding (to his Institution) to partially support his salary from Novartis, Pfizer, Merck, Roche, and AstraZeneca. Olivia Pagani reports no conflicts related to this trial., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Low steady-state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor-positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z-endoxifen and Z-4-hydroxy-tamoxifen (Z-4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n = 191) we confirmed an inferior BC -specific survival in patients with the previously described serum concentration threshold of Z-4OHtam ≤ 3.26 nm (HR = 2.37, 95% CI = 1.02-5.48, P = 0.039). The 'dose-response' survival trend in patients categorized to ordinal concentration cut-points of Z-4OHtamoxifen (≤ 3.26, 3.27-8.13, > 8.13 nm) was also replicated (P-trend log-rank = 0.048). Z-endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5-year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Targeted therapy for patients with HER2-positive (HER2+) breast cancer has improved overall survival, but many patients still suffer relapse and death from the disease. Intratumor heterogeneity of both estrogen receptor (ER) and HER2 expression has been proposed to play a key role in treatment failure, but little work has been done to comprehensively study this heterogeneity at the single-cell level. In this study, we explored the clinical impact of intratumor heterogeneity of ER protein expression, HER2 protein expression, and HER2 gene copy number alterations. Using combined immunofluorescence and in situ hybridization on tissue sections followed by a validated computational approach, we analyzed more than 13 000 single tumor cells across 37 HER2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER2-targeted treatment, enabling us to study tumor evolution as well. We found that intratumor heterogeneity for HER2 copy number varied substantially between patient samples. Highly heterogeneous tumors were associated with significantly shorter disease-free survival and fewer long-term survivors. Patients for which HER2 characteristics did not change during treatment had a significantly worse outcome. This work shows the impact of intratumor heterogeneity in molecular diagnostics for treatment selection in HER2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Purpose: The presence of disseminated tumor cells (DTCs) in bone marrow (BM) predicts survival in early breast cancer. This study explores the use of DTCs for identification of patients insufficiently treated with adjuvant therapy so they can be offered secondary adjuvant treatment and the subsequent surrogate marker potential of DTCs for outcome determination., Patients and Methods: Patients with early breast cancer who had completed six cycles of adjuvant fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy underwent BM aspiration 2 to 3 months (BM1) and 8 to 9 months (BM2) after FEC. Presence of DTCs in BM was determined by immunocytochemistry using pan-cytokeratin monoclonal antibodies. If one or more DTCs were present at BM2, six cycles of docetaxel (100 mg/m(2), once every 3 weeks) were administered, followed by DTC analysis 1 and 13 months after the last docetaxel infusion (after treatment). Cox regression analysis was used to evaluate disease-free interval (DFI)., Results: Of 1,066 patients with a DTC result at BM2 and available follow-up information (median follow-up, 71.9 months from the time of BM2), 7.2% were DTC positive. Of 72 docetaxel-treated patients analyzed for DTCs after treatment, 15 (20.8%) had persistent DTCs. Patients with remaining DTCs had markedly reduced DFI (46.7% experienced relapse) compared with patients with no DTCs after treatment (adjusted hazard ratio, 7.58; 95% CI, 2.3 to 24.7). The docetaxel-treated patients with no DTCs after treatment had comparable DFI (8.8% experienced relapse) compared with those with no DTCs both at BM1 and BM2 (12.7% experienced relapse; P = .377, log-rank test)., Conclusion: DTC status identifies high-risk patients after FEC chemotherapy, and DTC monitoring status after secondary treatment with docetaxel correlated strongly with survival. This emphasizes the potential for DTC analysis as a surrogate marker for adjuvant treatment effect in breast cancer., (© 2014 by American Society of Clinical Oncology.)

Radiotherapy (RT) is a central treatment modality for breast cancer patients. The purpose of our study was to investigate the DNA methylation changes in tumors following RT, and to identify epigenetic markers predicting treatment outcome. Paired biopsies from patients with inoperable breast cancer were collected both before irradiation (n = 20) and after receiving 10-24 Gray (Gy) (n = 19). DNA methylation analysis was performed by using Illumina Infinium 27K arrays. Fourteen genes were selected for technical validation by pyrosequencing. Eighty-two differentially methylated genes were identified in irradiated (n = 11) versus nonirradiated (n = 19) samples (false discovery rate, FDR = 1.1%). Methylation levels in pathways belonging to the immune system were most altered after RT. Based on methylation levels before irradiation, a panel of five genes (H2AFY, CTSA, LTC4S, IL5RA and RB1) were significantly associated with clinical response (p = 0.041). Furthermore, the degree of methylation changes for 2,516 probes correlated with the given radiation dose. Within the 2,516 probes, an enrichment for pathways involved in cellular immune response, proliferation and apoptosis was identified (FDR < 5%). Here, we observed clear differences in methylation levels induced by radiation, some associated with response to treatment. Our study adds knowledge on the molecular mechanisms behind radiation response., (© 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.)

Background and Purpose: Breast cancer is diagnosed worldwide in approximately one million women annually and radiation therapy is an integral part of treatment. The purpose of this study was to investigate the molecular basis underlying response to radiotherapy in breast cancer tissue., Material and Methods: Tumour biopsies were sampled before radiation and after 10 treatments (of 2 Gray (Gy) each) from 19 patients with breast cancer receiving radiation therapy. Gene expression microarray analyses were performed to identify in vivo radiation-responsive genes in tumours from patients diagnosed with breast cancer. The mutation status of the TP53 gene was determined by using direct sequencing., Results and Conclusion: Several genes involved in cell cycle regulation and DNA repair were found to be significantly induced by radiation treatment. Mutations were found in the TP53 gene in 39% of the tumours and the gene expression profiles observed seemed to be influenced by the TP53 mutation status.

During a six-year period, 17 patients younger than 20 years of age, with a final diagnosis of subacute osteomyelitis, were admitted to the Norwegian Radium Hospital because of an initial suspicion of primary malignant bone tumour. The most common localizations were the metaphyses of long bones (eight patients) and the clavicle (four patients). Pain was the dominating symptom. Common radiological findings were localized osteolysis and/or sclerosis, cortical bone destruction, periosteal reaction and an adjacent, often palpable soft tissue mass. Clinical signs of infection were generally absent, and a positive bacterial culture was obtained from the biopsy material in only one patient. Following extensive investigations, a malignant bone tumour (especially Ewing's sarcoma) remained a differential diagnosis, and open biopsy was indicated in all cases. The patient material illustrates the difficulty in distinguishing between subacute osteomyelitis and malignant bone tumours, and it is stressed that diagnostic investigations for this type of patients should be performed in an oncological centre with experience of bone tumours.