Comparison of characteristics of patients with lung cancer in U.K. primary care databases: Clinical Practice Research Datalink Aurum and GOLD.

INTRODUCTION: In recent years, the number of general practices contributing to the Clinical Practice Research Datalink (CPRD) database GOLD is decreasing. Therefore, for research questions addressing for instance novel treatments requiring up-to-date data, sample size will become an important consideration in study feasibility. In recent years, CPRD Aurum, containing information of practices that use EMIS software, has become an additional data source that is being used for CPRD studies. In order to establish whether Aurum is suited to act as data source for future studies in the field of lung cancer research, we aimed to compare characteristics between patients with lung cancer in Aurum and GOLD. METHODS: A retrospective study was performed comparing characteristics and overall survival (OS) of patients with lung cancer in Aurum and GOLD. To further evaluate similarity, hypothetical eligibility of these patients in Aurum and GOLD was compared for 11 randomized clinical trials (RCTs). RESULTS: Baseline characteristics registered in Aurum and GOLD were largely similar, with some clinically irrelevant differences for previous malignancies, deviant laboratory values and drug use. Median OS was 9.8 and 9.0 months for patients in Aurum and GOLD, respectively. Potential RCT eligibility varied between 49.4% and 79.5% and 49.1% and 78.1% for patients in Aurum and GOLD, respectively. Mortality rates and the comparison of the obtained HRs per hypothetical eligibility cohort per RCT were similar in Aurum and GOLD. CONCLUSION: This study showed that data of patients with lung cancer in Aurum and GOLD are largely comparable, suggesting that Aurum is suitable for future epidemiological lung cancer research.

Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer.

BACKGROUND: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSION: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST.

Factors related to patient-reported cosmetic outcome after breast-conserving therapy for breast cancer.

BACKGROUND: Multiple factors can affect cosmetic outcome after breast-conserving therapy. We investigated which combination of factors could optimally predict patient reported cosmetic outcome. METHODS AND MATERIALS: Dutch patients treated with BCT between 2008 and 2013 were retrospectively analysed. Demographics, tumour characteristics, and treatment-related factors were obtained from available digital medical records. Patients were asked to indicate their degree of cosmetic satisfaction using the Harvard scale. Both univariable and multivariable logistic regression analyses were performed to create a prediction model. RESULTS: The present study based on 220 patients shows that univariable analysis radiotherapy boost (OR 4.01 [1.85-8.70], p ≤ 0.001) and adjuvant chemotherapy (OR 2.67 [1.45-4.92], p = 0.002) were significantly associated with unsatisfactory cosmetic outcome. In multivariable analyses, only a radiotherapy boost remained significantly associated (OR 4.08 [1.76-9.49], p = 0.001) with poor cosmetic outcome, while adjuvant chemotherapy was no longer associated with it (OR 1.61 [0.81-3.24), p = 0.18). These two factors, together with tumour histology and lymph node staging, showed the highest predictive values, although the predictive property of the overall model was limited (AUC = 0.69). CONCLUSION: In the present study, a variety of factors is explored. However, a radiotherapy boost was the only factor that was independently associated with a poor cosmetic outcome after BCT. This finding can be used for counselling in daily clinical practice. Creation of a prediction model will require further investigation.

The relative effectiveness of eribulin for advanced breast cancer treatment: a study of the southeast Netherlands advanced breast cancer registry.

Background: Eribulin provided significant overall survival (OS) benefit in heavily pretreated advanced breast cancer patients in the EMBRACE trial. We investigated the use of eribulin in daily clinical practice, the relative effectiveness of eribulin versus non-eribulin chemotherapy, and the safety of eribulin in real-world patients included in the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry.Material and methods: Patients treated with eribulin and eligible patients for eribulin who received a different chemotherapy (i.e., non-eribulin group) in ten hospitals in 2013-2017 were included. A multivariate matching algorithm was applied to correct for differences in baseline characteristics between the groups, including the number of previous treatment lines. Progression-free survival (PFS) and OS of eribulin were compared with the matched non-eribulin group through Kaplan-Meier curves and multivariate Cox proportional hazard models. The occurrence of dose delay and reduction was described.Results: Forty-five patients received eribulin according to its registration criteria and 74 patients were eligible for eribulin but received non-eribulin chemotherapy. Matching increased the similarity in baseline characteristics between the eribulin and non-eribulin groups. Median PFS was 3.5 months (95% confidence interval (CI): 2.7-5.5) in the eribulin group and 3.2 months (95% CI: 2.0-4.8) in the matched non-eribulin group (adjusted hazard ratio (HR): 0.83, 95% CI: 0.49-1.38). Median OS was 5.9 months (95% CI: 4.6-11.0) and 5.2 months (95% CI: 4.6-9.5) in the eribulin and non-eribulin groups, respectively (adjusted HR: 0.66, 95% CI: 0.38-1.13). Dose delay or reduction occurred in 14 patients (31%) receiving eribulin.Conclusions: No difference in PFS and OS was observed between eribulin and non-eribulin treated patients. Eribulin had a manageable toxicity profile.

The influence of neoadjuvant chemotherapy on complications of immediate DIEP flap breast reconstructions.

PURPOSE: The impact of neoadjuvant chemotherapy on the surgical outcomes of immediate breast reconstruction remains controversial. The aim of this study was to analyze the incidence of complications of immediate deep inferior epigastric artery perforator (DIEP) flap breast reconstructions in patients who received neoadjuvant chemotherapy compared to patients without neoadjuvant chemotherapy prior to surgery. METHODS: A multicenter, retrospective cohort study was conducted of all patients who underwent immediate DIEP flap breast reconstruction between January 2010 and June 2017. Patients were divided in two groups as breast reconstructions with or without neoadjuvant chemotherapy, respectively. The primary outcome was the incidence of postoperative flap re-explorations, recipient-site complications and donor-site complications. RESULTS: In total 432 immediate DIEP flap breast reconstructions in 326 patients were included. Forty-eight patients (n = 67 flaps) received neoadjuvant chemotherapy prior to immediate breast reconstruction and 278 patients (n = 365 flaps) did not. No statistically significant differences for any major (4.5% vs. 10.4%; p = 0.175) or minor (16.4% vs. 24.7%; p = 0.191) recipient-site complication were observed. Donor-site complications were recorded in 9 (18.8%) and 62 (22.2%) patients, respectively (p = 0.587). There was no difference in need for flap re-exploration between groups (3.0% vs. 8.5%; p = 0.139). Correction for potential confounding variables did not result in significant differences. CONCLUSIONS: This study demonstrated similar complication rates for patients with and without neoadjuvant chemotherapy prior to immediate breast reconstruction, indicating that it is safe to perform an immediate DIEP flap breast reconstruction after neoadjuvant chemotherapy.

Population-based study of the effect of preoperative breast MRI on the surgical management of ductal carcinoma in situ.

BACKGROUND: Determinants of the use of breast MRI in patients with ductal carcinoma in situ (DCIS) in the Netherlands were studied, and whether using MRI influenced the rates of positive resection margins and mastectomies. METHODS: All women aged less than 75 years, and diagnosed with DCIS between 2011 and 2015, were identified from the Netherlands Cancer Registry. Multivariable logistic regression analyses were performed, adjusting for incidence year, age, hospital type, DCIS grade and multifocality. RESULTS: Breast MRI was performed in 2382 of 10 415 DCIS cases (22·9 per cent). In multivariable analysis, patients aged less than 50 years, those with high- or intermediate-grade DCIS and patients with multifocal disease were significantly more likely to have preoperative MRI. Patients undergoing MRI were more likely to have a mastectomy, either as first surgical treatment or following breast-conserving surgery (BCS) in the event of positive margins (odds ratio (OR) 2·11, 95 per cent c.i. 1·91 to 2·33). The risk of positive surgical margins after BCS was similar for those with versus without MRI. The secondary mastectomy rate after BCS was higher in patients who had MRI, especially in women aged less than 50 years (OR 1·94, 1·31 to 2·89). All findings were similar for low- and intermediate/high-grade DCIS. CONCLUSION: Adding MRI to conventional breast imaging did not improve surgical outcome in patients diagnosed with primary DCIS. The likelihood of undergoing a mastectomy was twice as high in the MRI group, and no reduction in the risk of margin involvement was observed after BCS.

ANTECEDENTES: Se estudiaron los determinantes del uso de la resonancia magnética (RM) de mama en pacientes con carcinoma ductal in situ (ductal carcinoma in situ, DCIS) en los Países Bajos y si el uso de la RM influía en las tasas de márgenes de resección positivos y de mastectomías. MÉTODOS: Todas las mujeres menores de 76 años de edad y diagnosticadas de DCIS fueron identificadas a partir del Registro de Cáncer de los Países Bajos de 2011-2015. Se realizaron análisis de regresión logística multivariable, ajustando por año de incidencia, edad, tipo de hospital, grado de DCIS y multifocalidad. RESULTADOS: Se realizó una RM de mama en 2.382 de 10.415 (23%) pacientes con DCIS. En el análisis multivariable, en las pacientes de edad < 50 años, con DCIS de grado alto o intermedio y enfermedad multifocal era estadísticamente significativo más probable que se sometieran a una RM preoperatoria. Las pacientes que se sometieron a RM tuvieron más probabilidades de que se efectuara una mastectomía, ya fuera como primer tratamiento quirúrgico o después de una cirugía conservadora de mama (breast conserving surgery, BCS) en el caso de presentar márgenes positivos (razón de oportunidades, odds ratio, OR = 2,1, i.c. del 95%: 1,9-2,3). El riesgo de obtener márgenes quirúrgicos positivos después de la BCS fue similar para aquellas pacientes con RM versus sin RM. Sin embargo, la tasa de mastectomía secundaria después de la BCS fue mayor en pacientes con RM, especialmente en mujeres menores de 50 años (OR = 1,9, i.c. del 95%: 1,3-2,9). CONCLUSIÓN: Agregar la RM a las imágenes radiológicas convencionales de mama no mejoró el resultado quirúrgico en pacientes diagnosticadas de DCIS primario. En el grupo de RM, la probabilidad de someterse a una mastectomía fue dos veces más alta, sin observarse una reducción en el riesgo de afectación del margen después de la BCS.

Counseling young women with early breast cancer on fertility preservation.

PURPOSE: Women with early-stage breast cancer may still have a future child wish, while chemotherapy may impair fertility. To pursue on fertility preservation shortly after breast cancer diagnosis is complex. This review holds a critical reflection on all topics that need to be counseled to give them the opportunity to make a well-informed decision before starting any oncological treatment. METHODS: A comprehensive literature review was performed on papers published in English language on breast cancer in young women, risk of chemotherapy-induced infertility, fertility preservation techniques, impact of possible mutation carriership, and future pregnancy outcome. RESULTS: Below 40 years of age, the risk of permanent chemotherapy-induced ovarian function failure is approximately 20%, where taxanes do not significantly add to this risk. Overall, 23% of reported women who performed fertility preservation by cryopreserving oocytes or embryos returned for embryo transfer. Of these, 40% gave live birth. Both fertility preservation in women diagnosed with breast cancer and pregnancy after treatment seem safe with respect to breast cancer survival. Women who have a genetic predisposition for breast cancer like BRCA gene mutation should also be informed about the possibility of pre-implantation genetic diagnosis. CONCLUSIONS: Women with an early stage of breast cancer and a possible future child wish should be referred to an expertise center in breast cancer, fertility preservation, and genetics in this complex decision-making process, shortly after diagnosis.

Non-visualized sentinel nodes in breast cancer patients; prevalence, risk factors, and prognosis.

BACKGROUND: Evidence and consensus is lacking in international guidelines regarding axillary treatment recommendations for patients in whom a sentinel lymph node (SLN) cannot be visualized (non-vSLN) during the sentinel node procedure. In this study we aimed to determine the prevalence of non-vSLNs in a Dutch population of breast cancer patients and to examine predictors and survival rate for non-vSLN. METHODS: A nationwide, retrospective, population-based study was performed including 116,920 patients with invasive breast cancer who underwent a SLN procedure in the Netherlands between January 2005 and December 2013. RESULTS: Of the 76,472 clinically negative patients who underwent a SLN procedure, 1924 patients (2.5%) had a non-vSLN, of whom 1552 (80.7%) underwent an ALND. Multivariate analysis showed predictive factors for non-vSLN: older age (p < 0.001), diagnosis in the period 2005-2009 (p < 0.001), larger tumor size (p = 0.003), and extensive nodal involvement (p < 0.001). Multivariate survival analysis showed a significantly worse survival (HR 1.18, 95% CI 1.03-1.34, p = 0.015) for non-vSLNs patients. However, in the non-vSLN group, an ALND was not statistically significantly associated with a better survival (HR 0.96, 95% CI 0.53-1.75, p = 0.891). CONCLUSION: Patients with non-vSLNs had less favorable disease characteristics and a worse survival compared to patients with a visualized SLN. Performing an ALND was not associated with a significantly better survival in patients with non-vSLNs. However, further research on the necessity of axillary treatment in this specific patient group is required.

Professionals' knowledge, attitude and referral behaviour of preimplantation genetic diagnosis for hereditary breast and ovarian cancer.

Hereditary breast and ovarian cancer caused by a BRCA1/2 mutation is the most frequent indication for preimplantation genetic diagnosis (PGD) in the Netherlands. The extent to which involved professionals are informed about this option, however, is unclear. The few available international studies mostly represent a limited range of professionals, and suggest that their knowledge about PGD for hereditary cancer syndromes is sparse and referral for PGD is based on limited understanding. A cross-sectional survey assessing awareness, knowledge, acceptability and PGD-referral for BRCA was completed by 188 professionals involved in the field of breast and ovarian cancer or reproduction. One-half of professionals were aware of PGD for BRCA, and most had a low to moderate level of knowledge. A total of 86% considered PGD for BRCA acceptable and 48% had referred patients with BRCA for PGD. Awareness and knowledge was higher among professionals who worked at a university hospital (compared with a general hospital). Knowledge of PGD was positively associated with discussing and referring for PGD, and PGD acceptability was associated with previous awareness. Although PGD counselling is the primary responsibility of the geneticist, other involved professionals may be gatekeepers as patients rely on them for raising awareness and referral.

Support needs of couples with hereditary breast and ovarian cancer during reproductive decision making.

OBJECTIVE: Reproductive decision making for couples with hereditary breast and ovarian cancer (HBOC) is complex and can result in decisional conflict or regret. This study investigated couples' support needs and aimed to identify vulnerable couples. Ultimately, we should strive to develop a clear standard of care guideline regarding reproductive decision support. METHODS: Mixed methods were used for data collection. A focus group study was conducted among 18 couples (N = 35) with HBOC who had made a reproductive decision after reproductive counselling. Subsequently, 129 similar couples (N = 258) were invited to complete a cross-sectional survey based on the focus group study. RESULTS: Clinical and practical aspects of reproductive counselling were positively evaluated in the focus group study, although couples indicated a need for additional support with emotional and social concerns in which their relationship, social environment, and the way they picture their desired family were key elements. The survey was completed by 86 participants. Making a reproductive choice was experienced as (very) difficult by 43%, and 69% showed a need for additional support during decision making. Younger participants and those who opted for a natural pregnancy experienced more difficulty with reproductive decision making, and partners showed a higher need for psychological support than carriers. CONCLUSIONS: Couples with HBOC who need to make a reproductive decision have specific needs for guidance and support, of which the desired content and methods can vary. It is therefore important to identify vulnerable couples and to attune counselling to couples' needs.

Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer.

PURPOSE: The INTENS study was designed to determine whether delivering neoadjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. METHODS: Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600-T 100 mg/m2) or six cycles of TAC as triplet chemotherapy (75/50/500 mg/m2) every 3 weeks. The primary outcome was the pathologic complete response (pCR), with disease-free and overall survival as secondary endpoints. RESULTS: In total, 201 patients were included. The pCR rates were 28% for patients treated with AC-T and 19% for patients treated with TAC, with an odds ratio of 1.60 (95% CI 0.90-3.21). With a median follow-up of 6 years (range 0.04-8.41 years), the five-year disease-free survival was 81% for patients treated with sequentially AC-T and 71% for patients treated with concurrent triplet TAC chemotherapy with a stratified hazard ratio (HR) of 0.50 (95% CI 0.29-0.86). Five-year overall survival was 84% versus 76%, respectively, with a stratified HR of 0.55 (95% CI 0.29-1.03). CONCLUSIONS: No differences were observed between the two treatment arms with respect to pCR rate, but the sequentially delivered chemotherapy outperformed the triplet combination chemotherapy in terms of survival, despite a lower cumulative dose per agent. GOV nr NCT00314977.

Awareness and attitude regarding reproductive options of persons carrying a BRCA mutation and their partners.

STUDY QUESTION: To what extent are BRCA mutation carriers and their partners in the Netherlands aware about preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) as reproductive options and what is their attitude towards these options? SUMMARY ANSWER: Awareness of PGD (66%) and PND (61%) among BRCA mutation carriers and their partners is relatively high and 80% and 26%, respectively, of BRCA carriers and their partners find offering PGD and PND for hereditary breast and ovarian cancer (HBOC) acceptable. WHAT IS KNOWN ALREADY: Internationally, awareness of PGD among persons with a genetic cancer predisposition appears to be relatively low (35%) and although acceptability is generally high (71%), only a small proportion of mutation carriers would consider using PGD (36%). However, for HBOC, there are no studies available that investigated the perspective of individuals with a confirmed BRCA1/2 mutation and their partners about PGD and PND including demographic and medical correlates of awareness and acceptability. STUDY DESIGN, SIZE, DURATION: A cross-sectional survey was completed by 191 participants between July 2012 and June 2013. Participants were recruited through patient organizations (88%) and the databases of two Clinical Genetics departments in the Netherlands (12%). PARTICIPANTS/MATERIALS, SETTING, METHODS: Male and female BRCA carriers and their partners completed an online survey, which assessed demographic and medical characteristics, and awareness, knowledge, acceptability and consideration of PGD and PND as main outcomes. Correlations between demographic and medical characteristics and the main outcomes were investigated. MAIN RESULTS AND ROLE OF CHANCE: The majority of respondents were female (87%), of reproductive age (86%) and about half reported a desire for a child in the future. About two-thirds (66%) were aware of PGD and 61% of PND for HBOC. PGD knowledge was moderate (5.5 on a 9-point scale) and acceptability of PGD and PND for HBOC was 80% and 26%, respectively. A minority would personally consider using PGD (39%) or PND (20%). Individuals with a higher educational level were more likely to be aware of PGD (P < 0.001) and PND (P < 0.001) and persons with a more immediate child wish were more often aware of PGD (P = 0.044) and had more knowledge about PGD (P = 0.001). PGD acceptability was positively associated with knowledge about PGD (P = 0.047), and PND acceptability was higher among partners in comparison to carriers (P = 0.001). Participants with a history of cancer and with a higher perceived seriousness of breast and ovarian cancer were more likely to consider using PGD (P = 0.003 and P < 0.001 respectively) or PND (P = 0.021 and P = 0.017 respectively). LIMITATIONS, REASONS FOR CAUTION: The response rate (23%) of participants invited by the clinical genetics departments was low, probably related to a simultaneous study that used a similar recruitment strategy within the same target group, which may have resulted in selection bias. Moreover, PGD knowledge was measured with an instrument that is not yet validated since to date such an instrument is not available in the literature. Finally, the cross-sectional design of this study limits us from drawing any causal conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Improvement of information provision remains needed, in order to timely inform all couples with HBOC about the available reproductive options and enable them to make a balanced reproductive decision. This may limit the risk of negative psychological impact due to decisional conflict and possible regret. STUDY FUNDING/COMPETING INTEREST(S): The Dutch breast cancer foundation Stichting Pink Ribbon (grant number 2010.PS11.C74). None of the authors have competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013-08).

BACKGROUND: Studies showed that axillary lymph node dissection can be safely omitted in presence of positive sentinel lymph node(s) in breast cancer patients treated with breast conserving therapy. Since the outcome of the sentinel lymph node biopsy has no clinical consequence, the value of the procedure itself is being questioned. The aim of the BOOG 2013-08 trial is to investigate whether the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients treated with breast conserving therapy. METHODS: The BOOG 2013-08 is a Dutch prospective non-inferiority randomized multicentre trial. Women with pathologically confirmed clinically node negative T1-2 invasive breast cancer undergoing breast conserving therapy will be randomized for sentinel lymph node biopsy versus no sentinel lymph node biopsy. Endpoints include regional recurrence after 5 (primary endpoint) and 10 years of follow-up, distant-disease free and overall survival, quality of life, morbidity and cost-effectiveness. Previous data indicate a 5-year regional recurrence free survival rate of 99% for the control arm and 96% for the study arm. In combination with a non-inferiority limit of 5% and probability of 0.8, this result in a sample size of 1.644 patients including a lost to follow-up rate of 10%. Primary and secondary endpoints will be reported after 5 and 10 years of follow-up. DISCUSSION: If the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients undergoing breast conserving therapy, this study will cost-effectively lead to a decreased axillary morbidity rate and thereby improved quality of life with non-inferior regional control, distant-disease free survival and overall survival. TRIAL REGISTRATION: The BOOG 2013-08 study is registered in ClinicalTrials.gov since October 20, 2014, Identifier: NCT02271828. https://clinicaltrials.gov/ct2/show/NCT02271828.

BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD.

PURPOSE: The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group. METHODS: A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching. RESULTS: Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0-9.0) in the BRCA group as a whole, 6.5 (IQR 4.0-8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5-9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0-11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). CONCLUSIONS: Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve.

Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives.

The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC.

Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET).

BACKGROUND: This European phase IIIb, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2. PATIENTS AND METHODS: Post-menopausal women aged ≥18 years with hormone receptor-positive, human epidermal growth factor-receptor-2-negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors were enrolled. The primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). The secondary objective was to evaluate AEs of grade 3/4 severity. RESULTS: The median treatment duration was 5.1 months [95% confidence interval (CI) 4.8-5.6] for EVE and 5.3 months (95% CI 4.8-5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXE-related or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported non-hematologic AEs were (overall %, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AEs were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly (≥70 years) versus non-elderly patients (23.8% versus 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related. CONCLUSIONS: This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. Although the patients were more heavily pretreated, the safety profile of EVE plus EXE in BALLET was consistent with BOLERO-2. CLINICAL TRIAL REGISTRATION: EudraCT Number: 2012-000073-23.

In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.

BACKGROUND: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. PATIENTS AND METHODS: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. RESULTS: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. CONCLUSIONS: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.

Differences in Response and Surgical Management with Neoadjuvant Chemotherapy in Invasive Lobular Versus Ductal Breast Cancer.

BACKGROUND: This study was conducted to determine the impact of neoadjuvant chemotherapy (NAC) on the likelihood of breast-conserving surgery (BCS) performed for patients with invasive lobular breast carcinoma (ILC) and invasive ductal carcinoma (IDC). METHODS: Female patients with a diagnosis of ILC or IDC in The Netherlands between July 2008 and December 2012 were identified through the population-based Netherlands Cancer Registry. RESULTS: A total of 466 ILC patients received NAC compared with 3622 IDC patients. Downstaging by NAC was seen in 49.7 % of the patients with ILC and in 69.6 % of the patients with IDC, and a pathologic complete response (pCR) was observed in 4.9 and 20.2 % of these patients, respectively (P < 0.0001). Breast-conserving surgery was performed for 24.4 % of the patients with ILC receiving NAC versus 39.4 % of the patients with IDC. In the ILC group, 8.2 % of the patients needed surgical reinterventions after BCS due to tumor-positive resection margins compared with 3.4 % of the patients with IDC (P < 0.0001). Lobular histology was independently associated with a higher mastectomy rate (odds ratio 1.91; 95 % confidence interval 1.49-2.44). Among the patients with clinical T2 and T3 disease, BCS was achieved more often when NAC was administered in ILC as well as IDC. CONCLUSION: The patients with ILC receiving NAC were less likely to experience a pCR and less likely to undergo BCS than the patients with IDC. With regard to BCS, the impact of NAC for ILC patients was lower than for patients receiving surgery without NAC. However, despite the high number to treating in order to achieve BCS, a small subset of ILC patients, especially cT2 and cT3 patients, still may benefit from NAC.

Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer?

BACKGROUND: We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients. METHODS: Consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy. RESULTS: Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49-2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy. CONCLUSION: Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.