There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17 917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7 years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] 1⁄4 1.04, 95% confidence interval [CI]1⁄40.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR1⁄40.68, 95% CI1⁄40.32 to 1.47, HR1⁄40.94, 95% CI1⁄40.70 to 1.26, and HR1⁄41.10, 95% CI1⁄40.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk. Several studies have reported evidence for a strong association between risk-reducing salpingo-oophorectomy (RRSO) and reduced breast cancer risk for BRCA1 and BRCA2 mutation carriers (1–4). Heemskerk-Gerritsen et al. (5), however, argued that these risk estimates were biased because of using an inappropriate analysis; they reported no association with breast cancer risk when RRSO was considered as a time-dependent covariate. Time-dependent analyses treat women as unexposed before RRSO and exposed after RRSO. Kotsopoulos et al. (6) confirmed the findings of Heemskerk-Gerritsen et al. (5) using a longer mean follow-up time (5.6 years vs 3.2 years). Both studies had few incident breast cancer cases among women with RRSO (122 and 21 among BRCA1 and BRCA2 mutation carriers, respectively, in Kotsopoulos et al. (6), and 36 and 6 among BRCA1 and BRCA2 carriers, respectively, in Heemskerk-Gerritsen et al. (5)), which limited power. We examined the association between RRSO and breast cancer risk for women across a wide range of familial and genetic risk using the Prospective Family Study Cohort (7). With our large cohort and long follow-up time, we were also able to investigate whether timing of RRSO mattered and whether use of hormone therapy after RRSO accounted for any lack of evidence for a decreased breast cancer risk. The Prospective Family Study Cohort includes women from the Breast Cancer Family Registry (BCFR) and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) (7). All participants provided written informed consent before enrollment, and study protocols have been approved by institutional review boards at each of the respective institutions. The current analysis used data from all women aged 18 to 79 years who were unaffected with breast B R IE F C O M M U N IC A T IO N Received: April 10, 2018; Revised: August 2, 2018; Accepted: September 7, 2018 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 331 JNCI J Natl Cancer Inst (2019) 111(3): djy182 doi: 10.1093/jnci/djy182 First published online November 28, 2018

Abstract Background: iPrevent (https://www.petermac.org/iprevent) provides women with highly-tailored risk management information after first estimating their breast cancer (BC) risk using the established risk prediction models, IBIS and BOADICEA. iPrevent has an internal switching algorithm that governs which model is used for each woman, depending on her risk factor data (i.e. LCIS/atypical hyperplasia status, BRCA status, and cancer family history). This study assessed the calibration and discriminatory accuracy of the 10-year BC risk estimates provided by iPrevent. Methods: Subjects were 16,574 women in the ProF-SC, aged 18-70 years and without BC or bilateral mastectomy at recruitment. After 10 years follow-up, 655 women (4%) were diagnosed with invasive BC. A “batch mode” for iPrevent is not available, so the iPrevent-assigned cumulative 10-year invasive BC risks were calculated by entering self-reported risk factors at cohort entry into either the IBIS (10,169 women) or BOADICEA (6,405 women) software packages (according to the iPrevent switching algorithm). To assess calibration, the mean iPrevent-assigned risk was compared with the mean 10-year observed invasive BC incidence, using a chi-squared goodness-of-fit statistic for the whole cohort, and by quartiles of risk. To evaluate discriminatory accuracy, the overall area under the receiver operating characteristic curve (AUC) for the development of invasive BC within 10 years was computed. Data were censored at date of invasive or in situ BC diagnosis, bilateral mastectomy, death, loss to follow-up, or at 10 years of follow-up. Results: For the whole cohort, iPrevent assigned risk was well-calibrated – 690 expected BCs (E) 655 observed (O) (E/O=1.05, 95% CI: 0.98-1.14), although for women in the highest risk quartile, i.e. >6% 10-year risk, E/O=1.19, 95% CI: 1.07-1.32. The AUC was 0.70, 95% CI: 0.68-0.72. Conclusions: iPrevent is well calibrated overall and has good discriminatory accuracy for predicting 10-year BC risk, thus justifying its clinical use. Citation Format: Phillips K-A, Liao Y, Collins IM, Buchsbaum R, Weideman P, Bickerstaffe A, MacInnis RJ, kConFab Investigators, Cuzick J, Antoniou A, Andrulis IL, John EM, Daly MB, Buys SS, Hopper JL, Terry MB. Validation of iPrevent using the prospective family study cohort (ProF-SC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-09-02.

Abstract This abstract was withdrawn by the authors.

Results:Six days following implantation of 2~10~ tumor cells, capillary sprouts were noted in the tumors.The take rate of the LS174T tumor in the chamber preparation was lOO%, and the tumor doubling time was 6.5 days.After ten days microcirculation in the tumors was established.Measurements of vessel density, vessel diameter and RBC velocity showed no changes in the control animals from day 10 to 22, whereas these parameters significantly increased in the LS174T tumors.Inflammatory reactions occurred only in lo-20% in the chamber preparations of the immunodeficient mice. Conclusion:To our knowledge, this is the first model enabling intravital microscopic studies on human tumors in an access chamber preparation.Studies on microcirculation and pathophysiologic changes following radiotherapy, as well as transport and distribution parameters of radiosensitizers in human tumors are in progress, and should provide new insights into the microcirculation mediated mechanisms of radiotherapy.

Elevated tumor interstitial fluid pressure (IFP) is believed to be responsible, at least in part, for the poor penetration and heterogeneous distribution of blood-borne therapeutic agents and nutrients in solid tumors. Using the wick-in-needle technique, IFP was measured in human patients with squamous cell carcinoma of the uterine cervix at the initial and final stages of fractionated external beam radiotherapy. Mean IFP values ranged from 10 to 26 mm Hg with an overall mean of 15.7 +/- 5.7 (SD) mm Hg in stage IIB and IIIB tumors (n = 12) and from 0 to 3 mm Hg in normal cervix (n = 3). IFP decreased in some patients with therapy while in others it increased. The changes in IFP values agree well with the clinical response to radiotherapy (n = 7, P less than 0.05). Oxygen tension, measured in selected tumors (n = 3) with polarographic oxygen microelectrodes, inversely correlated with IFP. These results show for the first time that the IFP in human cervical carcinomas is elevated, and that it can be lowered in some tumors using fractionated radiation therapy. These findings also suggest that IFP values may provide an indication of tumor oxygenation and that IFP modifications could be prognostic indicators of radiation response.