Bone metastasis in breast cancer: The story of RANK-Ligand

AbstractThe primary cellular mechanism responsible for osteolytic bone metastases is osteoclastic activation. Preclinical models have shown that breast cancer cells can produce parathyroid hormone-related protein (PTHrP), and other osteolytic molecules, which stimulate excessive osteoclastic bone resorption and establishment of osteolytic lesions. It has been shown that PTHrP by itself cannot directly induce osteoclastic activation, but it mediates its effect through the transactivation of RANK-ligand (RANKL) gene on stromal and osteoblastic cells. Accordingly RANKL up-regulation has been considered as a prerequisite in virtually all conditions of cancer induced bone destruction. Hence, therapeutic targeting of RANKL seems to be a rational approach to treat or even to prevent the process of bone metastases.In this review, we will focus on the unique patho-physiological aspects related to the evolution of bone metastases in breast cancer, emphasizing the pivotal role of RANKL and some other key molecules in osteoclastic bone resorption. We will discuss the therapeutic interventions using bisphosphonates and RANKL inhibitors in patients with bone metastases and the outcome of this novel approach

pregnancy in breast cancer survivors a need for proper counseling

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treatment of metastatic breast cancer during pregnancy we need to talk

Metastatic breast cancer during pregnancy is a challenging situation. The literature yield in this topic is poor given the rarity of the disease. Management strategies should be discussed in a multidisciplinary manner and each case have to be counselled separately and informed about the pros and cons of different treatment options. Here, we report a case of metastatic breast cancer initially diagnosed during pregnancy. We discuss the clinical course and dilemmas governing the management decisions

Biology of breast cancer in young women

Breast cancer arising at a young age is relatively uncommon, particularly in the developed world. Several studies have demonstrated that younger patients often experience a more aggressive disease course and have poorer outcome compared to older women. Expression of key biomarkers, including endocrine receptors, HER2 and proliferation markers, appears to be different in younger patients and young women are more likely to harbor a genetic predisposition. Despite these differences, little research to date has focused on the biology of these tumors to refine prognosis, and potentially direct treatment strategies, which remain similar to those offered to older patients. Accumulating evidence suggests the differences in breast stroma in younger patients and changes that occur with pregnancy and breastfeeding likely contribute to the different biology of these tumors. Reproductive behaviors appear to impact the biology of tumors developing later in life. In addition, tumors arising during or shortly following pregnancy appear to exhibit unique biological features. In this review, we discuss our emerging understanding of the biology of breast cancer arising at a young age at both the pathologic and the genomic level. We elucidate the potential role of genomic signatures, the impact of pregnancy and breastfeeding on breast cancer biology, and how even current knowledge might advance the clinical management of young breast cancer patients

Evaluation of horizontal ridge augmentation using beta tricalcium phosphate and demineralized bone matrix: A comparative study

Objectives: To evaluate the effectiveness of beta tricalcium phosphate (Beta-TCP) alone compared to Beta-TCP and Demineralized Bone Matrix (DBM) in regenerating localized horizontal maxillary alveolar ridge deficiencies prior to implant placement. Study Design: The study included 20 patients with horizontal maxillary ridge deficiencies limited to one or more neighbouring teeth and initial ridge width of . 5mmm. Patients were divided equally into two equal groups. Ridge augmentation was performed using Guided Bone Regeneration (GBR) principals. In group I GBR was performed using Beta-TCP only, while in group II both Beta-TCP and DBM were used. Following a 6 months healing period, bone cores from both groups were retrieved and implants were inserted. Specimens were examined histologically to calculate percentage of mineralized bone. Apical and crestal changes in ridge dimensions were calculated by digital subtraction using Cone Beam Computed Tomography (CBCT) immediately after graft placement and six months later. Results: There was a statistically significant difference between the mean area percentage of mineralized bone between both groups where it was 40.1 % (range: 27.76-% 66.29 %) for group I and 68.96 % (range: 60.07 % - 87.33 %) for group II. Radiograpically, the mean ridge width in group I increased crestally to 4.66 mm (range:3.5-5mm) and apically to 6.12 mm (range: 4.1-6.7 mm). In group II the mean ridge width increased crestally to 5.2 mm (range 4.9-5.4mm) and apically to 6.9 mm (range 6.0-7.8 mm). Group II showed more bone gain with a mean of 1.37 mm crestally and 2.44 mm apically. This difference however was not statistically significant Conclusion: Within the limitations of this study the combination of DBM and Beta-TCP can be used effectively in cases exhibiting minimal alveolar ridge defects

Tumour infiltrating lymphocytes (TILs) in breast cancer during pregnancy

Tumour infiltrating lymphocytes (TILs) is one of the most exciting breast cancer biomarkers, yet no data is available on its prevalence in tumours diagnosed during pregnancy.We evaluated the prevalence of TILs (stromal and intratumoural) in pregnant and non-pregnant young breast cancer patients.11/116 (9.6%) of the non-pregnant and 2/86 (2.3%) pregnant patients had TILs ≥ 50% (p 0.001) with highest prevalence observed in triple negative tumours (p = 0.01).This is the first report on TILs in tumours diagnosed during pregnancy. The low prevalence could reflect the state of low host immunity associated with pregnancy

Who are the women who enrolled in the POSITIVE trial: A global study to support young hormone receptor positive breast cancer survivors desiring pregnancy

Càncer de mama; Desig d'embaràs; Dones jovesBreast cancer; Pregnancy desire; Young womenCáncer de mama; Deseo de embarazo; Mujeres jóvenesBackground 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.The POSITIVE trial and this work are sponsored by the IBCSG in non-North American countries and by the Alliance for Clinical Trials in Oncology in North America, with collaboration of the Breast International Group (BIG) cooperative groups and US National Clinical Trials Network groups

breastfeeding in breast cancer survivors pattern behaviour and effect on breast cancer outcome

Abstract Little is known regarding the safety and feasibility of breastfeeding in women with a history of breast cancer. We have performed a survey among breast cancer patients who completed their pregnancy following breast cancer management to examine their lactation behaviours and its effect on breast cancer outcome. Out of 32 women identified, 20 were reachable and accepted to take the questionnaire. Ten women initiated breastfeeding, 4 stopped within one month and 6 had long-term success with a median period of 11 months (7–17 months). The latter were all previously subjected to breast conserving surgery and received qualified lactation counselling at delivery. The main reasons for not initiating breastfeeding were "uncertainty regarding maternal safety" and "a priori unfeasibility" expressed either by the obstetrician or by the oncologist. At a median follow-up of 48 months following delivery, all 20 women were alive with two relapses; one in each group (i.e., lactating and non-lactating). This analysis adds to the limited available evidence on the feasibility and safety of breastfeeding in breast cancer survivors. Proper fertility and survivorship counselling is crucial and requires more attention in breast cancer clinics

Breast cancer diagnosed during pregnancy is associated with enrichment of non-silent mutations, mismatch repair deficiency signature and mucin mutations

Breast cancer diagnosed during pregnancy (BCP) is a rare and highly challenging disease. To investigate the impact of pregnancy on the biology of breast cancer, we conducted a comparative analysis of a cohort of BCP patients and non-pregnant control patients by integrating gene expression, copy number alterations and whole genome sequencing data. We showed that BCP exhibit unique molecular characteristics including an enrichment of non-silent mutations, a higher frequency of mutations in mucin gene family and an enrichment of mismatch repair deficiency mutational signature. This provides important insights into the biology of BCP and suggests that these features may be implicated in promoting tumor progression during pregnancy. In addition, it provides an unprecedented resource for further understanding the biology of breast cancer in young women and how pregnancy could modulate tumor biology

Cancer and fertility preservation: International recommendations from an expert meeting

In the last years, thanks to the improvement in the prognosis of cancer patients, a growing attention has been given to the fertility issues. International guidelines on fertility preservation in cancer patients recommend that physicians discuss, as early as possible, with all patients of reproductive age their risk of infertility from the disease and/or treatment and their interest in having children after cancer, and help with informed fertility preservation decisions. As recommended by the American Society of Clinical Oncology and the European Society for Medical Oncology, sperm cryopreservation and embryo/oocyte cryopreservation are standard strategies for fertility preservations in male and female patients, respectively; other strategies (e.g. pharmacological protection of the gonads and gonadal tissue cryopreservation) are considered experimental techniques. However, since then, new data have become available, and several issues in this field are still controversial and should be addressed by both patients and their treating physicians. In April 2015, physicians with expertise in the field of fertility preservation in cancer patients from several European countries were invited in Genova (Italy) to participate in a workshop on the topic of "cancer and fertility preservation". A total of ten controversial issues were discussed at the conference. Experts were asked to present an up-to-date review of the literature published on these topics and the presentation of own unpublished data was encouraged. On the basis of the data presented, as well as the expertise of the invited speakers, a total of ten recommendations were discussed and prepared with the aim to help physicians in counseling their young patients interested in fertility preservation. Although there is a great interest in this field, due to the lack of large prospective cohort studies and randomized trials on these topics, the level of evidence is not higher than 3 for most of the recommendations highlighting the need of further research efforts in many areas of this field. The participation to the ongoing registries and prospective studies is crucial to acquire more robust information in order to provide evidence-based recommendations