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. 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. 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 %). 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.

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.

Radiation therapy is an indispensable part of various treatment modalities for breast cancer. Specifically, for non-inflammatory locally advanced breast cancer (LABC) patients, preoperative radiotherapy (pRT) is currently indicated as a second line therapy in the event of lack of response to neoadjuvant chemotherapy. Still approximately one third of patients fails to respond favourably to pRT. The aim of this study was to explore molecular mechanisms underlying differential response to radiotherapy (RT) to identify predictive biomarkers and potential targets for increasing radiosensitivity. The study was based on a cohort of 134 LABC patients, treated at the Institute of Oncology and Radiology of Serbia (IORS) with pRT, without previous or concomitant systemic therapy. Baseline transcriptional profiles were established using Agilent 60 K microarray platform in a subset of 23 formalin-fixed paraffin-embedded (FFPE) LABC tumour samples of which 11 radiotherapy naïve and 3 post-radiotherapy samples passed quality control and were used for downstream analysis. Biological networks and signalling pathways underlying differential response to RT were identified using Ingenuity Pathways Analysis software. Predictive value of candidate genes in the preoperative setting was further validated by qRT-PCR in an independent subset of 60 LABC samples of which 42 had sufficient quality for data analysis, and in postoperative setting using microarray data from 344 node-negative breast cancer patients (Erasmus cohort, GSE2034 and GSE5327) treated either with surgery only (20%) or surgery with RT (80%). We identified 192 significantly differentially expressed genes (FDR < 0.10) between pRT-responsive and non-responsive tumours, related to regulation of cellular development, growth and proliferation, cell cycle control of chromosomal replication, glucose metabolism and NAD biosynthesis II route. APOA1, MAP3K4, and MMP14 genes were differentially expressed (FDR < 0.20) between pRT responders and non-responders in preoperative setting, while MAP3K4 was further validated as RT-specific predictive biomarker of distant metastasis free survival (HR = 2.54, [95%CI:1.42–4.55], p = 0.002) in the postoperative setting. This study pinpoints MAP3K4 as a putative biomarker of response to RT in both preoperative and postoperative settings and a potential target for radiosensitising combination therapy, warranting further pre-clinical studies and prospective clinical validation.

Background/Aim. Regular physical activity and exercise improves quality of life and possibly reduces risk of disease relapse and prolongs survival in breast cancer survivors. The aim of this study was to evaluate the impact of a 3-week moderate intensity aerobic training, on aerobic capacity (VO2max) in breast cancer survivors. Methods. A prospective, randomized clinical study included 18 female breast cancer survivors in stage I-IIIA, in which the primary treatment was accomplished at least 3 months before the study inclusion. In all the patients VO2max was estimated using the Astrand?s protocol on a bicycle-ergometer (before and after 3 weeks of training), while subjective assessment of exertion during training were estimated by the Category-Ratio RPE Scale. Each workout lasted 21 minutes: 3 minutes for warmup and cool-down each and 15 min of full training, 2 times a week. The workload in the group E1 was predefined at the level of 45% to 65% of individual VO2max, and in the group E2 it was based on subjective evaluation of exertion, at the level marked 4-6. Data on the subjective feeling of exertion were collected after each training course in both groups. Results. We recorded a statistically significant improvement in VO2max in both groups (E1 - 11.86%; E2 - 17.72%), with no significant differences between the groups. The workload level, determined by the percent of VO2max, was different between the groups E1 and E2 (50.47 ? 7.02% vs 55.58 ? 9.58%), as well as subjective perception of exertion (in the groups E1 and E2, 11.6% and 41.6% of training, respectively, was graded in the mark 6). Conclusion. In our group of breast cancer survivors, a 3-week moderate intensity aerobic training significantly improved the level of VO2max.

Twelve premenopausal patients with advanced breast cancer were entered into pilot phase II study to assess efficacy, toxicity and influence of the synthetic LH-RH agonistic analogue D-Trp⁶-LH-RH (Decapeptyl®) on the patients’ hormonal status. The patients, aged 33-50, with newly diagnosed stage IV or recurrent breast cancer were not previously treated by any kind of endocrine therapy. Steroid receptor status was known in 9 patients. Decapeptyl was applied monthly at a dose of 3.75 mg i.m. until progression. The therapeutic response was evaluated in 11/12 patients. Partial remission was achieved in 5, stabilization in 3, and 3 consecutive patients failed to respond. The best therapeutic response was obtained in patients with pleuropulmonal and soft-tissue involvement, aged 41-45, including those with incomplete ovarian suppression, and regardless of steroid receptor status. The mean serum gonadotropins and estradiol levels were suppressed. The treatment was free of any side effects, except hot flushes in 7 patients.