Giulia Viglietti

Methods of controlled ovarian stimulation for embryo/oocyte cryopreservation in breast cancer patients

ABSTRACT Introduction: Controlled ovarian stimulation (COS) is a crucial step before oocyte collection and subsequent embryo/oocyte cryopreservation. However, in young breast cancer patients, the need for COS raises specific issues that should be taken into account during oncofertility counseling. Areas covered: We aim to perform an overview of COS protocols with a specific focus on the current knowledge and clinical challenges related to their use in young breast cancer patients. Expert commentary: Many protocols for COS are currently available to induce multiple follicular recruitment and maximize oocyte retrieval in women undergoing in vitro fertilization treatment. In cancer patients, to avoid the need to wait for a spontaneous menstruation, emergency protocols are also available so that COS can be started at any time during the menstrual cycle. COS protocols with the addition of tamoxifen or letrozole have been specifically designed for breast cancer patients to limit the potential negative impact of the temporary increase in estradiol levels during stimulation.

Risk of adverse events with the addition of targeted agents to endocrine therapy in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis

BACKGROUND Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting. METHODS A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents. We calculated summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) for each AE within each class of targeted agents for each trial, and pooled analysis using the random and fixed effect models. RESULTS Sixteen studies (n=8529 patients) were included. The addition of targeted agents to ET was associated with a significant higher risk of grade 3-4 AEs: OR 2.86 (95% CI 2.49-3.27) for CDK4/6 inhibitors, 1.88 (95% CI 1.39-2.53) for mTOR inhibitors, 2.05 (95% CI 1.63-2.58) for PI3K inhibitors, and 2.48 (95% CI 1.09-5.66) for anti-HER2 agents. The highest class-specific risks were neutropenia grade 3-4 for CDK4/6 inhibitors (OR 40.77; 95% CI 19.52-85.19), stomatitis grade 3-4 for mTOR inhibitors (OR 11.92; 95% CI 3.68-38.57), hyperglycemia grade 3-4 for PI3K inhibitors (OR 40.93; 95% CI 10.08-166.22) and diarrhea for anti-HER2 agents (OR 9.93; 95% CI 4.71-20.95). CONCLUSIONS Adding targeted agents to ET is associated with a significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used.

Pharmacotherapy to protect ovarian function and fertility during cancer treatment

In recent years, modern anticancer treatments have led to significant survival improvements; however, in premenopausal women, the administration of these therapies is also associated with potential unwanted side effects such as treatment-related premature ovarian failure (POF) and subsequent reduced fertility [1]. At the time of cancer diagnosis, the maintenance of gonadal function and fertility has crucial importance for many patients. As recommended by international guidelines, all patients of reproductive age should be counseled about the potential treatment-related loss of ovarian function and fertility and helped with informed fertility preservation decisions [2,3]. For young female cancer patients, embryo/oocyte cryopreservation are standard strategies to preserve fertility [2,3]; however, they require a period of controlled ovarian stimulation with subsequent delay in the initiation of anticancer treatments and they cannot preserve gonadal function during cytotoxic therapy. Pharmacological protection of the ovaries with the use of temporary ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy is a widely available option requiring no delay in the initiation of treatment. However, taking into account the controversial data available up to 2013, it was considered an experimental strategy in cancer patients [2,3]. Over the past few years, several important news have become available on the potential efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as a strategy to preserve ovarian function and fertility in young patients with breast cancer and lymphoma.

Potential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient’s Body Mass Index

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as analgesics in primary cancer surgery. Retrospective studies suggest that NSAIDs could reduce breast cancer recurrences. Because NSAIDs also act on biological mechanisms present in patients with increased adiposity, we aimed at assessing whether the intra-operative administration of ketorolac or diclofenac would be associated with a reduction of recurrence in patients with elevated body mass index (BMI). Methods We considered two institutional retrospective series of 827 and 1007 patients evaluating the administration of ketorolac (n = 529 with, n = 298 without) or diclofenac (n = 787 with, n = 220 without). The BMI subgroups were defined as less than 25 kg/m2 (lean) and 25 or more kg/m2 (overweight and obese). Cumulative incidence estimation of distant metastases as well as Fine-Gray and Dixon-Simon models was used. These analyses were adjusted for clinico-pathological variables. All statistical tests were two-sided. Results The administration of ketorolac was statistically significantly associated with decreased incidence of distant recurrences (adjusted hazard ratio [aHR]= 0.59, 95% confidence interval [CI] = 0.37 to 0.96, P = .03). In particular, the association was evident in the high-body mass index (BMI) group of patients (aHR = 0.55, 95% CI = 0.31 to 0.96, P = .04). The administration of diclofenac was not statistically significantly associated with decreased incidence of distant recurrences, either in the global population or in the BMI subgroups. Conclusions These results show that the intra-operative administration of ketorolac, but not diclofenac, is statistically significantly associated with a reduction of distant recurrences in patients with increased BMI. Altogether, this study points to a potentially important repositioning of ketorolac in the intra-operative treatment of patients with elevated BMI that, if prospectively validated, might be as impactful as and cheaper than adjuvant systemic anticancer therapies.

Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis

Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA-mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA-mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3–4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA-mutated HER2-negative metastatic breast cancer.

Controversies in oncology: which adjuvant endocrine therapy is to be given to premenopausal patients with hormone receptor-positive breast cancer?

Although young women with newly diagnosed breast cancer are at increased risk of developing more aggressive tumour subtypes as compared with older patients, most of them are diagnosed with hormone receptor-positive (ie, luminal-like) disease.1 Hence, the majority of premenopausal women with early stage breast cancer are candidates to receive adjuvant endocrine therapy. Young age is considered a risk factor for breast cancer recurrence and death, particularly in women with luminal-like breast cancer.2 Hence, the choice of the most appropriate adjuvant endocrine therapy is of crucial importance particularly in premenopausal patients. For more than two decades, tamoxifen alone has been considered the standard of care as adjuvant endocrine therapy for all premenopausal patients with hormone receptor-positive breast cancer.3 4 Nevertheless, in the last few years, the adjuvant endocrine treatment landscape of premenopausal patients with breast cancer has dramatically changed and the choice of the best approach to be used in this setting has become particularly complex. In fact, important new data on the role of ovarian function suppression (OFS) in addition to tamoxifen or its possible combination with an aromatase inhibitor (AI) have recently become available and should now be discussed with all premenopausal women candidates to receive adjuvant endocrine therapy.5 Two studies (the E-3193, INT-01426 trials and the Suppression of Ovarian Function Trial (SOFT)7 8) provided evidence on the role of OFS in addition to tamoxifen in these patients. In the E-3193, INT-0142 trial, 345 premenopausal women at low clinical risk of recurrence (use of chemotherapy was not allowed) were randomised to receive tamoxifen alone or tamoxifen plus OFS for 5 years.6 The SOFT randomly assigned 3066 premenopausal women to receive 5 years of tamoxifen alone, tamoxifen plus OFS or the AI exemestane plus OFS.7 8 In the primary analysis of the …