Breast Cancer Risk After Ovarian Stimulation for In Vitro Fertilization

The study by Dr van den Belt-Dusebout and colleagues1 investigated a debated aspect of reproductive medicine: breast cancer risk following ovarian stimulation for in vitro fertilization (IVF).2-5 The authors concluded that “these findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women”.1 However, some important points should be discussed. For about 23 % of women, sub-fertility diagnosis and number of IVF cycles were collected using a questionnaire since medical records were not available. This high rate threatens the reliability of results. It is not possible to compare a detailed report of official medical records with data deriving from subjective memory of treatments received many years before. This may be a strong bias, because reproductive medicine, IVF strategies and the pharmacological protocols have changed rapidly in the last decades. Dates of diagnosis and histology were reported but unfortunately not disease staging. It would be interesting to investigate if ovarian stimulation with the use of IVF techniques can promote the occurrence of biologically different types of breast cancer, as in the case of tamoxifen-related endometrial cancer, a neoplasia with better prognostic profile and outcome. Also, the authors reported that breast cancer risk decreased with more IVF cycles (7 or more compared with 1-2). They suggested as potential explanations that women treated with more IVF cycles received more hCG or had longer periods of down-regulation with low estradiol and progesterone levels, or the women requiring more IVF cycles were inherently different. It is difficult to provide a definitive conclusion since the clinical outcomes of IVF cycles were not reported. The decreased risk in women treated with many IVF cycles also could be related to the improvement of ovarian function after repeated endocrine stimulations. Infertility and infertility-related nulliparity must be considered as risk factors for breast cancer, and prolonged treatment of anovulatory or poor ovulatory cycles could be one approach for restoring normal ovarian activity and reducing breast cancer risk

RE: Universal tumor DNA BRCA1/2 testing of ovarian cancer: prescreening PARPi treatment and genetic predisposition

BRCA1/2 mutations play a predictive role in ovarian cancer risk evaluation. Moreover , patients are today being tested for BRCA1/2 mutations to select a tailored therapy too , because they could benefit from a treatment with PARP inhibitors (PARPi).Therefore in ovarian carcinomas (OCs), BRCA1/2 mutation testing is an important step in planning the correct therapeutic strategy in association with chemotherapy and anti VEGF agents. We read with great interest the paper submitted by Vos et al (1) which investigates the role of universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as prescreen for PARPi treatment and cancer predisposition. With the approach described by the authors, both hereditary and somatic aberrations affecting DNA BRCA1/2 could be quickly and correctly detected with tumor BRCA1/2 smMIP-based next generation sequence testing

Update on Poly-ADP-ribose polymerase inhibition for ovarian cancer treatment

Background: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12–18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors. Particularly, PARP inhibitors are active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated breast related cancer antigens (BRCA) function have HR deficiency, which is also present in a significant proportion of non-BRCA-mutated ovarian cancer (“BRCAness” ovarian cancer). The prevalence of germline BRCA mutations in EOC has historically been estimated to be around 10–15 %. However, recent reports suggest that this may be a gross underestimate, especially in women with high-grade serous ovarian cancer (HGSOC). Main body of the abstract: The emergence of the DNA repair pathway as a rational target in various cancers led to the development of the PARP inhibitors. The concept of tumor-selective synthetic lethality heralded the beginning of an eventful decade, culminating in the approval by regulatory authorities both in Europe as a maintenance therapy and in the United States treatment for advanced recurrent disease of the first oral PARP inhibitor, olaparib, for the treatment of BRCA-mutated ovarian cancer patients. Other PARP inhibitors are clearly effective in this disease and, within the next years, the results of ongoing randomized trials will clarify their respective roles. Conclusion: This review will discuss the different PARP inhibitors in development and the potential use of this class of agents in the future. Moreover, combination strategies involving PARP inhibitors are likely to receive increasing attention. The utility of PARP inhibitors combined with cytotoxic chemotherapy is of doubtful value, because of enhanced toxicity of this combination; while, more promising strategies include the combination with antiangiogenic agents, or with inhibitors of the P13K/AKT pathway and new generation of immunotherapy

Progesterone therapy in endometrial cancer

We read with interest the paper “All-cause mortality in young women with endometrial cancer receiving progesterone therapy” by Maria P. Ruiz et al (1). The authors reported that the use of primary progesterone therapy increased significantly from 2004 to 2014 and that utilization was less frequent in older women, white women, and women with unfavorable grading and substaging. Moreover, the authors note, “its use was associated with decreased survival, particularly in women with stage IB tumors“. The results of this large study deserve some critical considerations. Given the demographic and clinical characteristics of the population, it appears that relatively few women were treated with primary progesterone therapy compared to primary hysterectomy. This trend is likely to generate contradictory bias. While oral progesterone therapy has remained largely unmodified over the past 10 years, surgery has undoubtedly improved greatly in terms of oncological outcomes and safety, thanks to better surgeons, expertise and improved technology (laparoscopy, robot assisted surgery). Moreover, the use of progesterone-releasing intrauterine devices has largely increased in the last 10 years in early endometrial cancer. Unfortunately, we don't know how many women were treated with oral or intrauterine progesterone, nor do we know the type and timing of surgical approach in women who underwent primary hysterectomy. We don't know the criteria used to select candidates for surgery, immediately or after primary progesterone therapy. We don't know how many women receiving primary progesterone therapy were also treated with resective hysteroscopy and how many received hysterectomy after primary progesterone therapy. Likewise we have no information about pharmaceutical selections (dosing, progestional agents, treatment interruptions and changes). According to recent data, the absence of such information undermines reliability of study results. (2, 3). This is not a small thing since some studies suggest ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT that the levonorgestrel intrauterine device could be superior to oral progestogens in the control of endometrial cancer and complex atypical hyperplasia (4). And we have to consider that use of progesterone delivering intrauterine device was rapidly increasing in the last years for neoplastic disorders in young patients. But above all, the study does not associate unfavorable survival data, in women treated with primary progesterone therapy, with the possible presence of risk factors for cardiovascular, thromboembolic and metabolic events. This greatly limits the validity of the authors’ conclusions, especially considering the small sample sizes. According to the above comments, it seems hard to state that primary progesterone therapy is less safe and less effective than primary hysterectomy in women with early endometrial cancer

Niraparib in ovarian cancer. results to date and clinical potential

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened

Innovations in the treatment of ovarian cancer. Analysis of the therapeutic development: from platinum to immunotherapy

Ovarian cancer is the seventh most common cancer in women. The therapeutic approach provides for an appropriate integration between surgery and chemotherapy. Surgery is an important step for diagnosis, staging and therapy, aiming at the complete cytoreduction of all macroscopic visible disease. At the moment, adjuvant and first-line chemotherapy has as a standard the carboplatin-paclitaxel combination. Further, the addition of bevacizumab in the advanced stage (IIIB-IV) is strongly recommended. Despite the initial effectiveness, however, 70-80% of patients develop relapsed disease within the first two years and require subsequent treatment lines that have palliative, rather than curative purposes and that seek to reach a chronic state for the disease. Among the causes of recurrences, one of the most studied is related to the stem cells that, due to a quiescent state, are resistant to chemotherapy. The choice of these treatments must consider several factors, including the probability of extending the PFS and OS, the residual toxicity, symptoms control, and the improvement of quality of life, and always remains subject to platinum free interval (PFI). There are not standard therapy. Pegylated liposomal doxorubicin (PLD) as a single agent or in combination with other drugs is one of several treatment modalities that may be considered for relapsed ovaria cancer. In addition, in about 15% to 20% of epithelial tumors, there is a mutation of the BRCA1 and 2 genes. This is fundamental to identify immediately a therapeutic opportunity represented by PARP inhibitors. These drugs, such as olaparib and niraparib, used in maintenance after a previous platinum-response, even partial, have also shown in upfront an activity in BRCA wild type, homologous recombination deficent (HRD) and homologous recombination proficient (HRP). Therefore, after 20 years of chemotherapy alone, new targeted therapies are emerging that will help changing the therapeutic approach, making treatments increasingly personalized

Triple negative breast cancer: new perspectives for targeted therapies

Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death

Acrocyanosis, digital ischemia and acronecrosis as first manifestations of endometrial adenocarcinoma: case presentation and literature review

The association between digital ischemia and cancer is rarely reported in literature and the exact mechanism of this occurrence has not been completely understood. We report here a case of a 73 yearold woman who presented digital ischemia as first manifestation of endometrial adenocarcinoma. Reporting this rare clinical case and with a brief literature review, we recommend to consider an intensive search for primary and metastatic cancer in all patients who experience a digital ischemia, with the aim to early detect and treat the disease

Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer

Breast cancer is the most common type of malignancy diagnosed in women. In the metastatic setting this disease is still uncurable. Taxanes represent an important class of antitumor agents which have proven to be fundamental in the treatment of advanced and early-stage breast cancer, but the clinical advances of taxanes have been limited by their highly hydrophobic molecular status. To overcome this poor water solubility, lipid-based solvents have been used as a vehicle, and new systemic formulations have been developed, mostly for paclitaxel, which are Cremophor-free and increase the circulation time of the drug. ABI-007 is a novel, albumin-bound, 130-nm particle formulation of paclitaxel, free from any kind of solvent. It has been demonstrated to be superior to an equitoxic dose of standard paclitaxel with a significantly lower incidence of toxicities in a large, international, randomized phase III trial. The availability of new drugs, such as Abraxane®, in association with other traditional and non-traditional drugs (new antineoplastic agents and targeted molecules), will give the oncologist many different effective treatment options for patients in this setting