F. Poggio

Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies

BACKGROUNDnThe role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS).nnnMETHODSnA literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models.nnnRESULTSnA total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23-0.57; P < 0.001), yet with significant heterogeneity (I(2) = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41-0.73, P < 0.001) without heterogeneity (I(2) = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02-3.28, P = 0.041; I(2) = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49-2.04, P = 0.939; I(2) = 68.0%, Pheterogeneity = 0.044).nnnCONCLUSIONnTemporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis.

Chemotherapy-induced premature ovarian failure and its prevention in premenopausal breast cancer patients

Breast cancer accounts for more than one quarter of all malignant tumors diagnosed in women of reproductive age: every year, more than 25,000 new cases of invasive breast carcinoma are diagnosed in patients under the age of 45 years in the United States [1]. This is a relatively small proportion (approximately 11%) of all new cases of breast tumors; however, breast cancer in young women represents a public health problem due to both medical and psychosocial challenges unique to or accentuated by their age [2]. Due to the fact that young women with breast cancer have an increased risk of presenting with biologically aggressive types of tumors, the majority are candidates to receive antineoplastic treatments that include the use of chemotherapy [3]. A possible side effect of chemotherapy in premenopausal patients is the occurrence of premature ovarian failure (POF), resulting in temporary or permanent amenorrhea. Even in the presence or resumed regular menses after chemotherapy, patients are still at risk of developing early menopause due to the damage of cytotoxic therapy to their ovarian reserve [4]. The effects of chemotherapy on ovarian function are variable and are strongly affected by patients’ age at the time of treatment, type, and dose of chemotherapy [4]. The most common chemotherapy regimens used in the adjuvant or neoadjuvant treatment of breast cancer are associated with an intermediate risk of developing POF (40–60%) in patients aged 30–39 years; however, the same regimens are associated with a high risk of developing POF (more than 80%) in women older than 40 and a low risk (less than 20%) in those under the age of 30 [4]. The development of chemotherapy-induced POF is associated with improved survival outcomes in premenopausal breast cancer patients [5]. However, the loss of ovarian function negatively impacts on global health of young breast cancer survivors being associated with several side effects, such as hot flashes, sweats, breast pain or sensitivity, vaginal dryness, vaginal discharge, lack of sexual desire, and weight gain [6]. Moreover, strongly associated with the loss of ovarian function is the risk of infertility: fertility issues represent a major concern for young breast cancer patients and can also influence their treatment decisions [7]. Recent data from the Suppression of Ovarian Function Trial (SOFT) study demonstrated excellent survival outcomes in premenopausal breast cancer patients who resumed their ovarian function after chemotherapy and were treated with ovarian suppression for 5 years as part of adjuvant endocrine therapy [8]. Moreover, it has been recently shown that having a pregnancy after prior breast cancer diagnosis and treatment should be considered safe, also in patients with endocrine sensitive disease [9]. These findings highlight the importance of maintaining ovarian function and fertility of young breast cancer patients who are candidates to receive chemotherapy during their reproductive age. Embryo and oocyte cryopreservation are considered standard procedure for fertility preservation, but no proven methods for preservation of ovarian function are yet available [10,11]. According to the American Society of Clinical Oncology and European Society for Medical Oncology guidelines, the two available strategies with the potential to preserve gonadal function of breast cancer patients undergoing chemotherapy, i.e. ovarian tissue cryopreservation and pharmacological protection of the ovaries with the use of gonadotropin releasing hormone analogues (GnRHa) during cytotoxic therapy, are still considered experimental techniques [10,11]. Unlike cryopreservation of embryos or oocytes, ovarian tissue cryopreservation can save not only fertility but also hormonal gonadal function. Moreover, ovarian tissue cryopreservation has other potential advantages: it can be performed at any time during the menstrual cycle and no hormonal stimulation is required, thus no delay EXPERT REVIEW OF QUALITY OF LIFE IN CANCER CARE, 2016 VOL. 1, NO. 1, 5–7 http://dx.doi.org/10.1080/23809000.2016.1139458

Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis

BackgroundnThe role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients is highly controversial and it is not endorsed by current guidelines. Our meta-analysis aimed to better elucidate its activity, efficacy and safety.nnnMaterial and methodsnA systematic search of Medline, Web of Science and conferences proceedings up to 30 October 2017 was carried out to identify randomized controlled trials (RCTs) investigating platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients. Using the fixed and random effects models, pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for pathological complete response (pCR, defined as ypT0/is pN0), event-free survival (EFS), overall survival (OS) and grade 3 and 4 adverse events (AEs: neutropenia, anemia, thrombocytopenia and neuropathy).nnnResultsnNine RCTs (Nu2009=u20092109) were included. Overall, platinum-based neoadjuvant chemotherapy significantly increased pCR rate from 37.0% to 52.1% (OR 1.96, 95% CI 1.46-2.62, Pu2009<u20090.001). Platinum-based neoadjuvant chemotherapy remained significantly associated with increased pCR rate also after restricting the analysis to the three RCTs (Nu2009=u2009611) that used the same standard regimen in both groups of weekly paclitaxel (with or without carboplatin) followed by anthracycline and cyclophosphamide (OR 2.53, 95% CI 1.37-4.66, Pu2009=u20090.003). Conversely, among the 96 BRCA-mutated patients included in two RCTs, the addition of carboplatin was not associated with significantly increased pCR rate (OR 1.17, 95% CI 0.51-2.67, Pu2009=u20090.711). Two RCTs (Nu2009=u2009748) reported survival outcomes: no significant difference in EFS (HR 0.72, 95% CI 0.49-1.06, Pu2009=u20090.094) and OS (HR 0.86, 95% CI 0.46-1.63, Pu2009=u20090.651) was observed. A significant higher risk of grade 3 and 4 hematological AEs, with no increased risk of grade 3 and 4 neuropathy was observed with platinum-based neoadjuvant chemotherapy.nnnConclusionnIn TNBC patients, platinum-based neoadjuvant chemotherapy is associated with significantly increased pCR rates at the cost of worse hematological toxicities. Platinum-based neoadjuvant chemotherapy may be considered an option in TNBC patients.nnnPROSPERO registration numbernCRD42018080042.

The BCY3/BCC 2017 survey on physicians' knowledge, attitudes and practice towards fertility and pregnancy-related issues in young breast cancer patients

BACKGROUNDnFertility and pregnancy-related issues are major concerns for young breast cancer patients. Limited data are available on physicians knowledge, attitudes and practice in these fields.nnnMETHODSnA 26-item questionnaire exploring 3 different topics (fertility preservation, pregnancy after breast cancer and breast cancer during pregnancy) was sent by email to physicians attending the 2016 3rd European School of Oncology (ESO) - European Society for Medical Oncology (ESMO) Breast Cancer in Young Women Conference (BCY3) and the 15th St. Gallen International Breast Cancer Conference 2017 (BCC 2017). Given the selected sample, survey respondents were expected to have a higher than average interest in the management of breast cancer patients. Descriptive analyses were performed.nnnRESULTSnA total of 273 physicians (105u202fat BCY3 and 168u202fat BCC 2017) completed the survey; 37.0%, 46.9% and 34.8% reported never having consulted the available international guidelines on fertility preservation, pregnancy after breast cancer and management of breast cancer during pregnancy, respectively. Up to 18.3% of respondents did not know if the different fertility preservation options were available in their country; 22.3% suggested that controlled ovarian stimulation should not be considered safe in patients with hormone receptor-positive disease. A total of 30.4% of respondents agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence. Regarding breast cancer during pregnancy, 23.8% and 38.1% disagreed or were neutral on the statements that endocrine therapy and anti-HER2 agents should be avoided during pregnancy, respectively.nnnCONCLUSIONSnFurther educational initiatives are needed to improve physicians knowledge and adherence to available guidelines when addressing fertility and pregnancy-related issues in young breast cancer patients.

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.

Combination therapies for the treatment of HER2-positive breast cancer: current and future prospects

ABSTRACT Introduction: HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1, and neratinib, alone or combined in ‘dual HER2-blockade’ regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity, and cost-effectiveness. Expert commentary: The combination of trastuzumab/pertuzumab is approved in all disease settings, while trastuzumab/neratinib is approved in the adjuvant setting and trastuzumab/lapatinib in metastatic disease. Meanwhile, as breast cancer biology and resistance mechanisms become clearer, combinations with drugs like PI3K/Akt/mTOR inhibitors, CDK4/6 inhibitors, anti-PD(L)1 antibodies, endocrine therapy, and new anti-HER2 agents (panHER and HER2 tyrosine kinase inhibitors, bispecific antibodies, anti-HER3 antibodies, and antibody-drug conjugates) are being extensively tested in clinical trials. More specific strategies for the ‘triple-positive’ (estrogen receptor-positive/HER2-positive) disease are also being explored. However, there is an urgent need for the development of predictive biomarkers for a better tailoring of anti-HER2 directed therapy. This is the only way to further improve clinical outcomes and quality of life and to decrease costs and toxicities of unnecessary treatments.

Surgery of the primary tumour in patients presenting with de novo metastatic breast cancer: to do or not to do?

Approximately 5%–10% of patients with newly diagnosed breast cancer present with distant metastasis (ie, de novo metastatic disease).1 The appropriate clinical management of patients with de novo metastatic breast cancer is still very controversial; specifically, the need for radical locoregional treatment and its consequent benefit in this setting remains still highly debatable.nnIn 2012, a meta-analysis of 15 retrospective study including about 30u2009000 patients investigated the role of radical locoregional treatment of the primary tumour in patients with de novo metastatic breast cancer. The surgical resection of the primary breast tumour was independently associated with a statistically significant improvement in overall survival (OS; HR 0.69, 95% CI 0.63xa0toxa00.77, P<0.00001).2 Nevertheless, the reliability of the evidence deriving exclusively from retrospective studies can be limited due to several potential biases including the fact that patients who underwent surgery were often characterised by having a more limited metastatic dissemination, no (or limited) visceral involvement, younger age, better performance status and were selected for having had prior response to systemic therapy.nnRecently, three prospective randomised studies investigated the role of surgery of the primary tumour in patients with de novo metastatic breast cancer.3–5 However, conflicting results were reported. In the Indian trial, patients with de novo metastatic breast cancer were randomised to receive or not a radical locoregional surgical treatment in the absence of tumour progression after prior exposure to 6 months of an anthracycline/taxane-based chemotherapy. Patients were stratified according to site/number of distant metastases and hormonal receptor status. Surgery of the primary breast tumour did not improve OS (19.2 vs 20.5 months; P=0.79). On the contrary, distant progression free survival (PFS) of patients receiving radical locoregional treatment was significantly worse as compared …

Treatment-induced early menopause and the protective role of gonadotropin-releasing hormone agonists during chemotherapy

We read with great interest the recently published article by Zhang and colleagues reporting the results of their randomized phase III trial investigating the efficacy and safety of concurrent versus sequential administration of chemotherapy and the gonadotropin-releasing hormone agonist (GnRHa) goserelin in premenopausal women with estrogen receptor-positive breast cancer [1]. This study aimed at comparing the survival outcomes and the incidence of treatment-induced early menopause (defined as amenorrhea and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last GnRHa dose) between patients who received GnRHa for a duration of at least 2 years concurrently or sequentially to (neo)adjuvant chemotherapy. Among the 216 included patients, after a median follow-up of 56.9 months, no significant difference in disease-free survival (adjusted hazard ratio [HR] 1.52, 95% confidence intervals [CI] 0.80–2.86; p = 0.201) and overall survival (adjusted HR 1.62, 95% CI 0.51–5.16; p = 0.411) was observed between the two groups. Importantly, these findings are in the same line of other recent data on this topic [2, 3] further confirming that the concurrent use of a GnRHa and chemotherapy can be considered safe also in the subgroup of women with estrogen receptor-positive disease. On the other hand, to interpret the results of this trial in terms of protective gonadal effect of concurrent administration of GnRHa during chemotherapy is more complicated. Post-treatment ovarian function was assessed in 170 women (78.7% of the randomized patients): the incidence of treatment-induced early menopause was 22.8% in patients who did not receive GnRHa during chemotherapy and 23.1% in those who were treated with concurrent administration of the two therapies, a result that was not different between treatment arms (age-adjusted odds ratio [OR] 1.13, 95% CI 0.54–2.37; p = 0.737). Nevertheless, some crucial issues should be clarified for a better interpretation of these results. The authors assessed treatment-induced early menopause 1 year after the last GnRHa dose: notably, 47% of the included patients received approximately 2 years of GnRHa treatment while 53% were treated for at least 5 years. On the contrary, prior major trials that investigated the role of temporary ovarian suppression with GnRHa during chemotherapy assessed treatment-induced early menopause between 1 and 2 years after the end of the chemotherapy [3]. With this definition, the incidence of treatment-induced early menopause was 14.1% in patients treated with GnRHa during chemotherapy and 30.9% in those who received cytotoxic therapy alone, a result favoring the protective gonadal effect of this strategy (OR 0.38, 95% CI 0.26–0.57; p < 0.001) [3]. In the study by Zhang and colleagues, the time-point for the evaluation of treatment-induced early menopause after the end of chemotherapy is not clear considering the different duration of adjuvant GnRHa treatment among the included patients. Moreover, no data are presented on the number of women who were considered as having developed this side effect based on both menstrual function and hormone level assessment (as per primary study endpoint definition) or for whom amenorrhea only was used. In addition, notably, patients in the sequential arm could have received adjuvant GnRHa either immediately after the end of the chemotherapy or after the resumption of menstruation; therefore, a separate evaluation of treatment-induced early menopause in these two subgroups of patients would be important to be assessed for a clearer comparison with patients who * Matteo Lambertini matteo.lambertini85@gmail.com

HM35 Role of temporary ovarian suppression obtained with GnRH analogue in reducing premature ovarian failure induced by chemotherapy in premenopausal cancer patients: a meta-analysis of randomized studies

OR34 Sexual functioning in young women with breast cancer S. Rosenberg *, R. Tamimi, S. Gelber, K. Ruddy, S. Kereakoglow, V. Borges, S. Come, L. Schapira, E. Winer, A. Partridge. Harvard School of Public Health, Department of Epidemiology, Boston, USA, Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, USA, University of Colorado-Denver, Department of Medical Oncology, Denver, USA, Beth Israel Deaconess Medical Center, Department of Medical Oncology, Boston, USA, Massachusetts General Hospital, Department of Medical Oncology, Boston, USA