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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

The policing of rape and serious sexual offences (RASSO) is increasingly under scrutiny, with rising reporting rates, high attrition rates, and ever-decreasing charge and conviction rates. Internationally there appear to be common inadequacies in RASSO investigations. Given these issues, policing specialism may be an effective tool to improve the investigation of RASSO. This article systematically draws together the existing literature from around the world on the use of a specialist approach to tackling RASSO. A systematic literature review was conducted, and 18 papers were included for analysis based on the inclusion/exclusion criteria. From these documents, five key themes were found: investigation procedures and processes; victim care; specialist training, knowledge and skills; officer wellbeing and capacity; and policing outcomes. The review highlighted that the specialist policing of RASSO can improve the investigative process on several levels: improving the efficacy of the individual components of the investigation; better engagement with victims; better officer wellbeing; and overall improved policing outcomes. Further research is required into the specific mechanisms that results in improvements into the investigative process, the set-up of such specialist units, as well as how training in this area can be as effective as possible.

Background In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. Methods This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. Results Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). Conclusion Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842 .

Purpose Irosustat is a first-generation, orally active, irreversible steroid sulfatase inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to a first-line aromatase inhibitor (AI) in patients with advanced BC to evaluate the safety of the combination and to test the hypothesis that the addition of Irosustat to AI may further suppress estradiol levels and result in clinical benefit. Experimental design Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had derived clinical benefit from a first-line AI and who subsequently progressed were enrolled. The first-line AI was continued and Irosustat (40 mg orally daily) added. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included safety, tolerability, and pharmacodynamic end points. Results Twenty-seven women were recruited, four discontinued treatment without response assessment. Based on local reporting, the CBR was 18.5% (95% CI 6.3–38.1%) on an intent to treat basis, increasing to 21.7% (95% CI 7.4–43.7%) by per-protocol analysis. In those patients that achieved clinical benefit (n = 5), the median (interquartile range) duration was 9.4 months (8.1–11.3) months. The median progression-free survival time was 2.7 months (95% CI 2.5–4.6) in both the ITT and per-protocol analyses. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). Conclusions The addition of Irosustat to aromatase inhibitor therapy resulted in clinical benefit with an acceptable safety profile. The study met its pre-defined success criterion by both local and central radiological assessments. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4328-z) contains supplementary material, which is available to authorized users.

Background Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8mg/kg loading dose, then 6mg/kg every 3weeks (q3w)] and pertuzumab (840mg loading dose, then 420mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54years; 29% had received prior trastuzumab. Median treatment duration was 16months for pertuzumab and trastuzumab and 4months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. ClinicalTrials.gov NCT01572038.

Introduction: oncosurgical safety of therapeutic mammaplasty (TM) is widely investigated. The interval between surgery and delivery of adjuvant chemotherapy is an integral part of overall oncological safety. Therefore, we examined the time between TM and AC, and compared it to wide local excision (WLE) and mastectomy (Mx) with or without immediate breast reconstruction (IBR), respectively. Methods: data of 174 patients who underwent TM, WLE and Mx±IBR was analyzed retrospectively. All patients were operated within three breast units of Glasgow during a period of 48 months. Time between decision to offer adjuvant chemotherpay and delivery of the first cycle of chemotherapy was analyzed. Significance was calculated with Mann-Whitney and Kruskal-Wallis tests (two and four groups compared, respectively). Results: median time to adjuvant chemotherapy after TM (n = 36) was 29 [16–58] days, WLE (n = 66) was 29.5 [15–105], Mx only (n = 56) was 29 [15–57], and Mx and IBR (n = 16) was 31 [15–58] days. No significant difference was found in terms of time to adjuvant chemotherpay in patients treated with TM compared to WLE (p = 0.384), Mx only (p = 0.828) or Mx and IBR (p = 0.366). Further, there was no significant difference when a cumulative comparison of the four groups was carried out (p = 0.507). Conclusions: our data indicate that oncosurgical safety of TM in terms of time to chemotherapy is similar to other high risk breast cancer patients treated WLE and Mx with or without IBR. This also suggests that there is no significant difference in postoperative complication rates after these four ways of surgical treatment of breast cancer, which would possibly be the primary cause for a delay in delivering adjuvant chemotherapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-14-13.

BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mgm(-2) q3w, paclitaxel 80mgm(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175mgm(-2) q3w. The primary endpoint was safety/tolerability.RESULTS: A total of 116 patients received saracatinib 125 (N - 20), 175 (N - 44), 225 (N - 40), 250 (N - 9), or 300mg (N - 3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade >= 3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; >= 225 mg, 33%), and grade >= 3 neutropenia occurred more commonly at doses >= 225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.CONCLUSION: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.British Journal of Cancer (2012) 106, 1728-1734. doi:10.1038/bjc.2012.158 www.bjcancer.com Published online 24 April 2012 (C) 2012 Cancer Research UK

To define the variability of menstrual cycle length and contribution of follicular and luteal phases to overall cycle variability, and to examine the rise in urinary hCG in early pregnancy.Menstrual cycle study. Urine samples from 101 women (recruited from two south-east counties in the UK) were assayed to determine day of luteinising hormone (LH) surge, lengths of follicular and luteal phases and correlations with total menstrual cycle length. HCG study. Daily urine samples collected from 86 women prior to conception until 43 days post-conception were assayed for hCG and examined versus time since LH surge, determined using fertility test kits.Mean menstrual cycle length was 27.7 +/- 3.4 days, mean follicular phase length was 14.5 +/- 3.4 days and mean luteal phase length was 13.2 +/- 1.9 days. Total cycle lengths varied between and within women. There was a significant correlation (r(2) = 0.70) between follicular phase length and total cycle length; luteal phase length was less variable and showed no association with total cycle length. Concentrations of hCG were significantly similar between women when referenced against the day since LH surge. Three thresholds were determined to indicate time since conception as 1-2 weeks, 2-3 weeks and 3+ weeks.Total cycle length variation is mainly determined by follicular phase variation and predicting menses onset to estimate time of pregnancy testing is unreliable. Evaluating concentrations of hCG relative to LH surge results in consistent increases between women up to 21 days after conception. Therefore, urinary hCG concentration can be used to accurately estimate time since conception.

(Pre)malignant lesion in the breast requiring mastectomy conventionally may be treated with breast conservation by using oncoplastic breast surgical techniques, which is called therapeutic mammaplasty. However, no reliable data has been published so far as regards the oncological safety of this method.The aim of the authors was to analyse the oncological safety of therapeutic mammaplasty in a series of patients.99 patients were treated with therapeutic mammaplasty and data were collected in a breast surgical database prospectively. Results were analysed with respect to intraoperative, postoperative and long-term oncological safety.Incomplete resection rate was 14.1%, which correlated with tumour size (p = 0.023), and multifocality (p = 0.012). Time between surgery (therapeutic mammaplasty) and chemotherapy was similar to time between conventional breast surgeries (wide excision, mastectomy, mastectomy with immediate reconstruction) and chemotherapy (mean 29-31 days; p0.05). Overall recurrence rate was 6.1%, locoregional recurrence rate was 2% during 27 month (1-88) mean follow-up.Since literature data are based on relatively short follow-up and low patient number, it is highly important that all data on therapeutic mammaplasty is collected in a prospectively maintained breast surgical database in order to determine true recurrence after long-follow-up.Bevezetés: Az onkoplasztikai emlősebészeti módszerek alkalmazásával a hagyományosan mastectomiával kezelt (pre)malignus emlőelváltozások is eltávolíthatók emlőmegtartó műtéttel (terápiás emlőplasztika). A módszer onkosebészeti megbízhatóságára ugyanakkor nincsenek megfelelő adatok. Célkitűzés: A szerzők célul tűzték ki a terápiás emlőplasztika onkosebészeti biztonságának meghatározását. Módszer: 99 beteget kezeltek terápiás emlőplasztikával és az eredményeket folyamatosan vezetett emlősebészeti adatbázis alapján elemezték. Az intraoperatív, a közvetlen posztoperatív, illetve a hosszú távú onkológiai biztonságot vizsgálták. Eredmények: A betegek 14,1%-ában voltak a reszekciós szélek inkomplettek, amelyek korreláltak a tumormérettel (p = 0,023) és a multifokális elváltozásokkal (p = 0,012). A terápiás emlőplasztika és a kemoterápia megkezdése közötti időintervallum hasonló volt a mastectomiával, egyszerű széles excisióval, vagy mastectomiával és azonnali rekonstrukcióval kezelt betegekéhez (átlagosan 29–31 nap; p0,05). 27 hónapos (1–88) átlagos utánkövetési idő alatt a recidíva aránya 6,1%, ebből a lokális recidíva aránya 2% volt. Következtetések: Mivel az irodalmi adatok is hasonlóan rövid utánkövetési időszakon és alacsony betegszámon alapulnak, kulcsfontosságú, hogy minden emlőcentrum, ahol terápiás emlőplasztikát végeznek, folyamatosan vezetett adatbázist készítsen a hosszú távú recidívaarány meghatározása céljából. Orv. Hetil., 2013, 154, 1291–1296.

549Background: Lowering estradiol levels is a key treatment modality for estrogen-receptor positive (ER+) postmenopausal breast cancer (BC).Currently, only one of the two main enzymes for oestrogen...

Purpose The DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (decitabine) induces DNA demethylation and re-expression of epigenetically silenced genes, and increases carboplatin sensitivity of tumor xenograft models. We designed a clinical study to determine the feasibility of delivering a dose of decitabine, combined with carboplatin, that would be capable of producing equivalent biologic effects in patients with solid tumors. Patients and Methods In a two-stage design, 33 patients received escalating doses of decitabine administered as a 6-hour infusion on day 1 followed by carboplatin, area under the concentration-time curve (AUC) 5 (cohort 1) and AUC 6 (cohort 2), on day 8 of a 28-day cycle. Pharmacodynamic analyses included 5-methyl-2′-deoxycytidine levels, MAGE1A CpG island methylation, and fetal hemoglobin (HbF) expression. Results The major toxicity was myelosuppression. Dose limiting toxicities, prolonged grade 4 neutropenia (one patient), and sepsis and grade 3 anorexia/fatigue (one patient), were seen in two of four patients treated with decitabine 135 mg/m2 and carboplatin AUC 5. Dose limiting toxicity comprising neutropenic sepsis (one patient) and grade 3 fatigue (one patient) was seen in two of 10 patients treated at decitabine 90 mg/m2 and carboplatin AUC 6. Decitabine induced dose-dependent, reversible demethylation in peripheral-blood cells (PBCs) maximally at day 10. Furthermore, decitabine 90 mg/m2 induced demethylation of the MAGE1A CpG island in PBCs, buccal cells, and tumor biopsies, as well as elevation of HbF expression. Conclusion Decitabine can be combined safely with carboplatin at a dose and schedule that causes epigenetic changes equivalent to or greater than that observed in mice with carboplatin-sensitized xenografts. The recommended dose/schedule for phase II trials is decitabine 90 mg/m2 (day 1) followed by carboplatin AUC 6 (day 8) every 28 days.

Introduction: Subgroups within sporadic triple negative breast cancers (TNBCs) appear to share impaired DNA damage response mechanisms with BRCA1/2 mutation-associated breast cancers. This has been hypothesised to confer particular sensitivity to DNA-damaging platinum chemotherapy. The TNT trial, a randomized phase III trial in women with metastatic or recurrent locally advanced TNBC or BRCA1/2 mutation-associated breast cancer, aimed to test this hypothesis and examine treatment effect in biological subgroups. Patients & Methods: Eligible patients had either ER-, PR-, HER2- breast cancer or were known BRCA1/2 carriers (any ER/PR/HER2). Patients were randomized (1:1) to receive either C (AUC 6 q3wk) or D (100mg/m2 q3wk) for 6-8 cycles or until disease progression if sooner and could cross over to the alternative treatment on confirmed progression. Ineligible patients included those who had ECOG performance status >2, received adjuvant taxane therapy in the last 12 mths, any previous treatment with a platinum chemotherapy, or previous non-anthracycline chemotherapy for metastatic disease. For consenting patients a blood sample and archived tissue samples were obtained for BRCA1/2 genotyping and central biomarker analysis (primary tumour, lymph nodes and recurrent tumour biopsy if available) of subtypes within TNBC and biomarkers of DNA repair deficiency. The primary endpoint was RECIST objective tumour response up to cycle 6 of randomised treatment. Secondary endpoints included toxicity, progression free survival (PFS), time to progression and overall survival. TNT aimed to detect a 15% improvement in ORR with C compared to D, with planned target sample size range of 370-450 depending on assumed ORR in D patients (2-sided α=0.05, power=90%). 376 (188 C, 188 D) were recruited from 74 UK centres between Apr 08 and Mar 14. Results: A snapshot of the data was taken on 30/5/14 at which point 336 (89.4%) patients had experienced a PFS event, with overall median PFS time of 4.4 mths. Median age of patients was 55 yrs (IQR 48-63). 366/376 (97%) patients had TNBC of whom 18 were also known BRCA1/2 mutation carriers, with the remaining 10 patients receptor +ve and BRCA1/2 carriers. 338/376 (90%) had metastatic and 38/376 (10%) recurrent locally advanced disease. 53% had liver or lung metastases affecting the parenchyma and 34% had received previous adjuvant taxane therapy. Median time from initial diagnosis to entering TNT was 2.2 yrs (IQR 1.5-3.5). Primary tumour tissue has currently been received for 277 patients, blood from 286 patients and recurrent tumour tissue from 85 patients. Discussion: TNT will report evidence on the activity of single agent platinum chemotherapy compared with single agent taxane in patients with TNBC and BRCA1/2 associated breast cancer. Correlative analyses of BRCA1/2 mutation status, subtypes and DNA repair biomarkers will also be reported. TNT will be the first randomised trial to report the activity of platinum compared with standard chemotherapy within TNBC subtypes and in relation to BRCA1/2 mutation status and DNA repair biomarkers. Safety, tolerability and response to crossover treatment will also be presented. Citation Format: Andrew Tutt, Paul Ellis, Lucy Kilburn, Cheryl Gilett, Sarah Pinder, Jacinta Abraham, Sophie Barrett, Peter Barrett-Lee, Stephen Chan, Maggie Cheang, Mitch Dowsett, Lisa Fox, Patrycja Gazinska, Anita Grigoriadis, Alexander Gutin, Catherine Harper-Wynne, Matthew Hatton, Sarah Kernaghan, Jerry Lanchbury, James Morden, Julie Owen, Jyoti Parikh, Peter Parker, Nazneen Rahman, Rebecca Roylance, Adam Shaw, Ian Smith, Rose Thompson, Kirsten Timms, Holly Tovey, Andrew Wardley, Gregory Wilson, Mark Harries, Judith Bliss. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-01.