Neoadjuvant Endocrine Research Articles

Abstract P6-17-05: Independent validation of a combined biomarker based on the PAM50 HER2-enriched subtype and ERBB2 mRNA levels following HER2 blockade without chemotherapy in the PerELISA phase II trial

Abstract Background: A combined biomarker based on HER2-enriched subtype (HER2-E) and ERBB2 mRNA predicts response and survival in HER2+ breast cancer following trastuzumab +/- lapatinib in the absence of chemotherapy (Prat et al. ASCO 2018). Here, we tested the ability of the combined biomarker to predict pathological complete response (pCR) following neoadjuvant trastuzumab, pertuzumab and endocrine therapy. Methods: RNA from 40 baseline tumor samples from the phase II PerELISA trial were evaluated. PerELISA evaluated the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen based on dual HER2 blockade with trastuzumab and pertuzumab in combination with letrozole in HER2+/hormone receptor-positive breast cancer selected on the basis of Ki67 response after short course letrozole-alone (Guarneri ASCO 2018). Ki67 response was defined by protocol as relative Ki67 reduction ≥20% from baseline at day 14. Gene-expression was measured using the nCounter platform. Intrinsic subtypes and ERBB2 levels were determined by the PAM50 gene expression predictor. A pre-specified ERBB2 cutoff was determined to define ERBB2-high. Univariate and multivariable logistic regression analyses were performed. Results: The proportion of HER2-E disease within the ERBB2-high and ERBB2-low groups was 46.2% (6/13) and 18.5% (5/27), respectively. The discordance rate at the individual level was 30% (12/40). A total of 6 (15%) and 34 (85%) samples were HER2-E/ERBB2-high and others, respectively. The magnitude of Ki67 reduction of the HER2-E/ERBB2-high and others groups was 64.8% and 63.2%, respectively (p=0.88). The pCR rate of HER2-E/ERBB2-high was 66.7%. The pCR rate of the others group was 14.7%. The univariate odds ratio between HER2-E/ERBB2-high tumors and the others groups was 11.60 (95% CI 1.66-81.10; p=0.014). No other clinical-pathological variable was significantly associated with pCR. Conclusion: The combined HER2-E/ERBB2-high biomarker can identify patients who might be good candidates to receive dual HER2 blockade alone without chemotherapy. Citation Format: Prat A, Griguolo G, Dieci MV, Bisagni G, Frassoldati A, Bianchi GV, Pascual T, Pare L, Galvan P, Urso L, Conte P, Guarneri V. Independent validation of a combined biomarker based on the PAM50 HER2-enriched subtype and ERBB2 mRNA levels following HER2 blockade without chemotherapy in the PerELISA phase II trial [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 P6-17-05.

Abstract P5-13-04: Needle-to-knife wait time and impact on pCR in patients undergoing neoadjuvant chemotherapy for breast cancer

Abstract Introduction: In the setting of pre-operative neoadjuvant chemotherapy (NAC) for the treatment of breast cancer, it is important to ensure coordination between medical and surgical oncology. A study by Sanford et al. show that patients receiving surgery >8 weeks after NAC have worse overall survival. As NAC continues to expand its role in breast cancer treatment, a closer look at the maximal acceptable time between NAC and surgery becomes more important. We wished to assess the impact of time between last dose of chemotherapy and surgery on pathological complete response (pCR), disease free survival (DFS), overall survival (OS), and surgical complications. Methods: A cohort study was conducted utilizing the BC Cancer Agency's prospective neoadjuvant database, located in Vancouver, BC. Patients were selected if they had undergone NAC with curative intent for treatment of breast cancer, followed by surgical resection. Patients who received neoadjuvant radiation and/or hormone therapy were excluded. Patients were divided into three groups: those who had surgery <4 weeks from last dose of chemo, 4-8 weeks from last dose, and >8 weeks from last dose. Charts were audited for demographic data, tumour characteristics, and complications from surgery. Data was analyzed using a Chi Squared test to determine any differences in pCR, OS, DFS, and surgical complications, between the three different time intervals. Results: 347 patients were identified and included in this study. The median time to surgery after last dose of chemotherapy was 4.86 weeks (range 0.86-22.86 weeks). The percentage of patients that achieved pCR was 31.3%, 30.5%, and 28.6% in the <4 weeks, 4-8 weeks, and >8 weeks groups respectively (p= NS for all comparisons). There was no difference in pCR observed between the three groups based on receptor status. At the median follow up of 3 years, DFS was 85%, 85.8%, and 85.7% in all three groups. Likewise OS was 95%, 90%, and 89% respectively. The rate of surgical complications are 16%, 23.4%, and 21.4% for the three groups respectively (p=NS). Conclusions: This study demonstrated no difference between receiving surgery <4 weeks, 4-8 weeks, or >8 weeks after last dose of NAC on pCR, survival, or surgical complications. This finding was preserved in all receptor subtypes. This has important implications for resource allocation. This data may also help in counselling and easing patient anxiety in terms of the urgency (or lack thereof) and wait times for surgery. Subsequent studies with larger sample sizes will help to ensure that clinical differences in outcomes are not affected by wait times. Comparison of outcome measures based on needle to knife time < 4 weeks (n=80)4-8 weeks (n=239)>8weeks (n=28)p (<4 weeks vs. < 8 weeks)pCR31.3% (25)30.5% (73)28.6% (8)0.791HR+Her2-4.5% (1/22)6.5% (6/92)0% (0/5)--TNBC31.5% (6/19)42.1% (24/57)0% (0/6)--Her2+46.1% (18/39)48.8% (44/90)47.1% (8/17)--3 year DFS85%85.5%85.7%0.9273 year OS95%90%89%0.290Surgical Complication16.3%23.4%21.4%0.536 Citation Format: Lai V, Hajjaj O, Chia S, Simmons C. Needle-to-knife wait time and impact on pCR in patients undergoing neoadjuvant chemotherapy for breast cancer [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 P5-13-04.

Prognostic relevance of DNA damage and repair biomarkers in elderly patients with hormone-receptor-positive breast cancer treated with neoadjuvant hormone therapy: evidence from the real-world setting.

Background:The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT).Methods:Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered.Results:The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature (p = 0.011). In models of Ki-67 reduction, ‘luminal B’ subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant (p < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival (p = 0.027) and overall survival (p = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades (p < 0.05 for both).Conclusions:We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms.

A Case Report of an 82-year-old Breast Cancer Patient who Achieved a Pathological Complete Response by Neoadjuvant Hormone Therapy

A Case Report of an 82-year-old Breast Cancer Patient who Achieved a Pathological Complete Response by Neoadjuvant Hormone Therapy

Effect of Neoadjuvant Hormone Therapy on Resection Margin and Survival Prognoses in Locally Advanced Prostate Cancer after Prostatectomy Using Propensity-Score Matching.

This study aimed to investigate the effect of neoadjuvant hormone therapy (NHT) on resection margin positivity, biochemical-recurrence- (BCR-) free survival, and overall survival (OS) in 176 patients with locally advanced prostate cancer (LAPC) treated with radical prostatectomy using propensity-score matching, including 79 (44.9%) patients treated with the NHT. Fifty pairs of one-to-one propensity-score matching were matched to investigate the pure effect of NHT on resection margin positivity, BCR, and OS with a statistical significance of p<0.050. Before matching, NHT, tumor volume percentage, and extracapsular extension were significant factors for resection margin positivity (p≤0.001); however, after matching, NHT became insignificant in the multivariate analysis (p=0.084). In the survival analysis, NHT was not associated with BCR or OS before and after matching (BCR: hazard ratio, 1.35 and 0.84, respectively; OS: hazard ratio, 1.05 and 0.77, respectively; p≥0.539 for all). Conversely, PSA level (HR, 2.23), extracapsular extension (HR, 2.10), and lymphovascular invasion (HR, 1.85) were significant factors for BCR (p≤0.001 for all), but none were significant factors for OS in the propensity-score matching analysis (p≥0.948). Therefore, NHT was not a significant factor for resection margin positivity, BCR-free survival, and OS before and after propensity-score matching in patients with LAPC.

Clinicopathologic features and prognosis analysis for stage pT0 prostate cancer after radical prostatectomy

Objective To analyze the clinical and pathological characteristics and prognosis of stage pT0 prostate cancer patients after radical prostatectomy. Methods From November 2004 to May 2017, eight patients who underwent radical prostatectomy and postoperatively diagnosed with pT0 were retrospectively evaluated.The patients aged 63-75 years (mean 69.1 years), with PSA 2.26-14.10 ng/ml(mean 6.10 ng/ml), prostate volume 30.3-72.1ml(mean 52.1ml). Exclusion criteria included patients undergoing neoadjuvant hormone therapy or TURP before the operation. Stage pT0 prostate cancer was defined as no evidence of residual tumor in radical prostatectomy specimen from the patient in whom biopsy-proven prostate carcinoma was histologically diagnosed. The clinical and pathological data were reviewed and follow-up was performed for stage pT0 prostate cancer patients. Biochemical progression was defined as postoperative PSA greater than 2 ng/ml for twice.The patients were followed-up. Results Eight patients(1.1%) were postoperatively diagnosed with prostate cancer of pT0 stage. After radical prostatectomy specimen was re-examined by an uropathological expert, small residual tumor(2mm) was found in left peripheral zone of the prostate in one patient. The average follow-up duration was 75 months for this 8 pT0 patients. One patient died of pulmonary embolism after 5 days of the surgery. No patient had evidence of biochemical progression. No biochemical recurrence survival rate and cancer-specific survival rate was 100%(7/7) and overall survival rate was 87.5%(7/8) for pT0 prostate cancer patients. Conclusions For patients who were biopsy-proven prostate cancer without neoadjuvant hormone therapy, stage pT0 was a rare pathological phenomenon. Those patients had a very favourable oncological prognosis. Key words: Prostatic neoplasm; Histopathological outcome; pT0 stage

Changes in prostate apparent diffusion coefficient values during radiotherapy after neoadjuvant hormones.

Changes in prostate cancer apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (MRI) provide a noninvasive method for assessing radiotherapy response. This may be attenuated by neoadjuvant hormone therapy (NA-HT). We investigate ADC values measured before, during and after external beam radiotherapy (EBRT) following NA-HT. Patients with ⩾T2c biopsy-proven prostate cancer receiving 3 months of NA-HT plus definitive radiotherapy were prospectively identified. All underwent ADC-MRI scans in the week before EBRT, in the third week of EBRT and 8 weeks after its completion. Imaging was performed at 1.5 T. The tumour, peripheral zone (PZ) and central zone (CZ) of the prostate gland were identified and median ADC calculated for each region and time point. Between September and December 2014, 15 patients were enrolled (median age 68.3, range 57-78) with a median Gleason score of 7 (6-9) and prostate-specific antigen (PSA) at diagnosis 14 (3-197) ng/ml. Median period of NA-HT prior to first imaging was 96 days (69-115). All patients completed treatment. Median follow up was 25 months (7-34), with one patient relapsing in this time. Thirteen patients completed all imaging as intended, one withdrew after one scan and another missed the final imaging. PZ and CZ could not be identified in one patient. Median tumour ADC before, during and post radiotherapy was 1.24 × 10-3 mm2/s (interquartile range 0.16 × 10-3 mm2/s), 1.31 × 10-3 mm2/s (0.22 × 10-3 mm2/s), then 1.32 × 10-3 mm2/s (0.13 × 10-3 mm2/s) respectively (p > 0.05). There was no significant difference between median tumour and PZ or CZ ADC at any point. Gleason score did not correlate with ADC values. Differences in ADC parameters of normal and malignant tissue during EBRT appear attenuated by prior NA-HT. The use of changes in ADC as a predictive tool in this group may have limited utility.

Stage T3b prostate cancer diagnosed by seminal vesicle biopsy and treated with neoadjuvant hormone therapy, permanent brachytherapy and external beam radiotherapy

To report the long-term results of prostate brachytherapy followed by external beam radiotherapy (EBRT) in men with a positive seminal vesicle biopsy (+SVB). In all, 1081 men with localised prostate cancer were treated with permanent brachytherapy, of which 615 had staging SVB and 53 (9.4%) were positive. Higher stage, Gleason score and PSA level were associated with a +SVB (P < 0.001). Patients with +SVB and negative laparoscopic pelvic lymph node dissection, bone and CT scans had 3 months of androgen-deprivation therapy (ADT) followed by 103 Pd implant to the prostate (dose 100 Gy) and proximal SVs, and 2 months later 45 Gy EBRT. ADT was continued for a median of 6 months (total ADT 9 months). The mean (range) follow-up was 9 (5-22) years. Biochemical freedom from failure (computed by the Phoenix definition), freedom from metastasis, and cause-specific survival (CSS) for patients with a negative SVB (-SVB) vs +SVB at 15 years, was 76.3% vs 60.6% (P = 0.001), 95.4% vs 78.2% (P < 0.001), and 95% vs 70.4% (P < 0.001), respectively. Prostate cancer death occurred in 45 of 590 (7.6%) men with a -SVB vs eight of 25 (32%) with a +SVB (odds ratio 5.7, 95% confidence interval 2.35-13.9, P < 0.001). Cox proportion hazard rates (HRs) demonstrated Gleason score (P < 0.001, HR 1.9), stage (P = 0.010, HR 1.42), RT dose (P = 0.013, HR 0.991), and +SVB (P = 0.001, HR 4.48), as significantly associated with CSS. Men with a +SVB have inferior CSS compared to those with a -SVB. However, a strategy that included a SVB in high-risk patients and implantation of the SVs in men undergoing combined therapy still yields favourable long-term results.

SABCS 2017 pathology: from bench to bedside.

SummaryThe 40th International San Antonio Breast Cancer Symposium offered a multifaceted platform for the presentation of several innovative therapeutic approaches. The results of these preclinical and clinical studies provided insight into the development of novel therapy concepts from the laboratory bench to the bedside of breast cancer patients. One main focus of last year’s symposium was the search for synergisms and opportunities for collaboration between basic research scientists and investigators in drug development. Highlights of these topics included preclinical data on selective estrogen receptor covalent antagonists (SERCAs), the discovery of immune-modulating effects of demethylating agents as well as the exact characterization and risk assessment of BRCA2 mutations of previously unknown significance. Pathological advances aimed at the molecular understanding of intratumoral heterogeneity and the evolution of lobular breast cancer. Beyond preclinical discoveries at the molecular level, clinical studies provided evidence on the duration of adjuvant bisphosphonate treatment and the use of the EndoPredict multigenomic assay to predict response to neoadjuvant chemo- and endocrine therapy. The SUCCESS A study reported that the prolonged adjuvant administration of zoledronic acid for 5 years did not improve patient survival after chemotherapy. A translational analysis of the ABCSG 34 trial revealed that the EndoPredict multigenomic assay could identify patients who do not benefit from neoadjuvant endocrine or chemotherapy. These recent advances are likely to promote individualized breast cancer care.

Development of a Ready-to-Use Graphical Tool Based on Artificial Neural Network Classification: Application for the Prediction of Late Fecal Incontinence After Prostate Cancer Radiation Therapy

This study was designed to apply artificial neural network (ANN) classification methods for the prediction of late fecal incontinence (LFI) after high-dose prostate cancer radiation therapy and to develop a ready-to-use graphical tool. In this study, 598 men recruited in 2 national multicenter trials were analyzed. Information was recorded on comorbidity, previous abdominal surgery, use of drugs, and dose distribution. Fecal incontinence was prospectively evaluated through self-reported questionnaires. To develop the ANN, the study population was randomly split into training (n=300), validation (n=149), and test (n=149) sets. Mean grade of longitudinal LFI (ie, expressed as the average incontinence grade over the first 3years after radiation therapy) ≥1 was considered the endpoint. A suitable subset of variables able to better predict LFI was selected by simulating 100,000 ANN configurations. The search for the definitive ANN was then performed by varying the number of inputs and hidden neurons from 4 to 5 and from 1 to 9, respectively. A final classification model was established as the average of the best 5 among 500 ANNs with the same architecture. An ANN-based graphical method to compute LFI prediction was developed to include one continuous and n dichotomous variables. An ANN architecture was selected, with 5 input variables (mean dose, previous abdominal surgery, use of anticoagulants, use of antihypertensive drugs, and use of neoadjuvant and adjuvant hormone therapy) and 4 hidden neurons. The developed classification model correctly identified patients with LFI with 80.8% sensitivity and 63.7%±1.0% specificity and an area under the curve of 0.78. The developed graphical tool may efficiently classify patients in low, intermediate, and high LFI risk classes. An ANN-based model was developed to predict LFI. The model was translated in a ready-to-use graphical tool for LFI risk classification, with direct interpretation of the role of the predictors.

EXOSOMAL MICRO-RNA - POTENTIAL PREDICTIVE MARKER OF BREAST CANCER NEOADJUVANT THERAPY EFFECT

Neoadjuvant systemic treatment of patients with breast cancer (BC) may include neoadjuvant chemotherapy (NHT), neoadjuvant hormone therapy (NGT), neoadjuvant targeted therapy. The type of systemic therapy is determined by the level of expression of estrogen/progesterone receptors, HER2, i.e. immunohistochemical characteristic of the disease. In this article, we evaluated the predictive value of the profile of plasma exosomal microRNA, assessing the immediate efficacy of NHT, which included taxanes. Obtained results revealed a correlation between the level of concentration of several miRNA molecules in circulating exosomes and the effect of NHT. Furthermore, the index calculated as the ratio of miR-34a and miR-451 concentrations, allowеd to predict the effect of taxanecontaining NHT. The results confirm the assumption on the predictive significance of exosomal miRNA. Further research is needed to confirm the validity of a new method of prediction of the NHT efficacy in breast cancer.

Factors influencing long-term urinary symptoms after prostate brachytherapy.

To determine which patient and treatment-related factors are associated with increased American Urological Association symptom score (AUASS) in men who presented with minimal symptoms before treatment for prostate cancer by permanent seed implantation. Of 1842 men with a minimum follow-up of 5years (mean 9.4), 1110 (60.3%) had an initial AUASS of 0-7 and were treated with brachytherapy (BT) alone (n = 491) or BT with neoadjuvant hormone therapy (NHT) and/or external beam radiation therapy (EBRT, n = 619). The median prostate volume was 37mL. Data were prospectively collected on comorbidities. Initial AUASS was compared to last using a Student's t-test (two-tailed). Freedom from increasing from minimal to moderate or severe symptoms was determined by the Kaplan-Meier method with comparisons by log-rank and Cox hazard rates (HRs). The change from pre-treatment score for the minimal, moderate and severe symptom groups was: 3.6-7.3 (P < 0.001), 11.6-11.3 (P = 0.426), and 24.1-16.9 (P < 0.001). For those with minimal symptoms the 10- and 15-year estimates for freedom from worse symptoms were 72.9% and 39.1%, respectively. Cox HRs were significant for EBRT boost (HR 1.45, P = 0.004), RT dose >200 Gy2 (HR 1.25, P = 0.024), hypertension (HR 1.37, P= 0.006), and alcohol use (HR 1.46, P = 0.001). A substantial number of men with initial low AUASS treated by BT experience worsening urinary symptoms with long-term follow-up. Use of EBRT, RT dose, hypertension and alcohol use are risk factors for an increase in urinary symptom score.

MELATONIN AND METFORMIN IN NEOADJUVANT HORMONOTHERAPY IN LOCALLY ADVANCED BREAST CANCER

Materials and methods. The effect of melatonin (MLT) and metformin (MTF) on the efficacy of neoadjuvant hormone therapy with toremifene was investigated in 54 patients with estrogen receptor-positive, locally advanced breast cancer (ER + BC). The average age of women was 67 years. The patients had no diabetes mellitus. The first group of patients (n = 19) received toremifene 120 mg per day, the second group (n = 16) - toremifene in combination with MLT 3 mg orally every night, the third group (n = 19) - toremifene in combination with MTF 850 mg twice daily. Randomization was performed - 1: 1: 1. The duration of therapy in all study groups was 4 months. After the end of treatment, all patients were undergone surgery. Further adjuvant treatment depended on the results of the postoperative pathomorphological conclusion. The primary endpoint was a decrease in the Ki-67% level (a surrogate marker for the effectiveness of hormone therapy), the secondary endpoints were the objective response, a pathological response in the tumor and lymph nodes, and the quality of life. Results. In all patients (n = 54), the frequency of decrease Ki-67 level and the frequency of objective response were 57% and 50%, respectively. At the same time, the incidence of Ki-67% level decrease in the «toremifene» group was 42%, in the «toremifene+MLT» group - 56%, in the «toremifene+MTF» group - 74%. Multifactor analysis showed that the addition of MTF to toremifene increases the chances of reducing Ki-67 compared with control 4.2 times (RR 4.23 [95% CI 1,04417,139], p = 0.043). It is important that only in the patients of the «toremifene+MTF» group a significant correlation was found between the Ki-67 index decrease in the tumor and the BMI value above the norm (p = 0.015). A complete pathomorphological response in the tumor and lymph nodes was not achieved in any patient. The objective response in the study groups was 31.6%, 86.7% and 47.3%, respectively. The addition of MLT to hormone therapy with toremifene significantly increased the frequency of the objective response from 31.6% to 86.7% (x2 = 10.32, p = 0.001). The inclusion into neoadjuvant hormone therapy with toremifene of MLT or MTF did not reduce the quality of life of patients, while in 50% of patients in the «toremifene+MLT» group there was an improvement in sleep.

MP22-19 PREDICTION AND STRATIFICATION OF THE BIOCHEMICAL RECURRENCE IN PATIENTS WITH HIGH-RISK PROSTATE CANCER AFTER LOW DOSE RATE PERMANENT SEED IMPLANTATION

You have accessJournal of UrologyProstate Cancer: Localized: Radiation Therapy1 Apr 2018MP22-19 PREDICTION AND STRATIFICATION OF THE BIOCHEMICAL RECURRENCE IN PATIENTS WITH HIGH-RISK PROSTATE CANCER AFTER LOW DOSE RATE PERMANENT SEED IMPLANTATION Yu Ozawa, Masanori Hasegawa, Noriaki Santo, Yasuto Yagi, Toru Nishiyama, Ryo Yabusaki, Keisuke Aoki, Ken Nakamura, Choichiro Ozu, Kazuhito Toya, Masanori Yorozu, and Shiro Saito Yu OzawaYu Ozawa More articles by this author , Masanori HasegawaMasanori Hasegawa More articles by this author , Noriaki SantoNoriaki Santo More articles by this author , Yasuto YagiYasuto Yagi More articles by this author , Toru NishiyamaToru Nishiyama More articles by this author , Ryo YabusakiRyo Yabusaki More articles by this author , Keisuke AokiKeisuke Aoki More articles by this author , Ken NakamuraKen Nakamura More articles by this author , Choichiro OzuChoichiro Ozu More articles by this author , Kazuhito ToyaKazuhito Toya More articles by this author , Masanori YorozuMasanori Yorozu More articles by this author , and Shiro SaitoShiro Saito More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.730AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Treatment of high-risk prostate cancer (PCa) remains challenging for urologists. The present study was undertaken to identify risk factors for the biochemical recurrence (BCR) in patients with high-risk PCa who underwent low dose rate permanent seed implantation brachytherapy with iodine-125 (LDR). METHODS Medical records of 335 patients with high-risk PCa identified by NCCN risk stratification treated with LDR during the period of 2004-2015 at our institution have been reviewed. All patients received extra beam radiation therapy after LDR. Possible risk factors assessed for the future BCR included age, PSA, prostate volume, histological findings of biopsy specimens, neoadjuvant hormone therapy and local extent of disease evaluated by pelvic MRI. BCR free survival rates were constructed using the Kaplan-Meier method. Risk factors for BCR were evaluated by the log-rank test and multivariate Cox proportional hazard model with a stepwise selection procedure. RESULTS The Kaplan-Meier analysis showed that the 5- or 10-year BCR free survival rates were 86.7%, and 78.8%, respectively. Multivariate analysis demonstrated that grade group 5 (Hazard ratio; HR 3.75, p<0.01), cT3 (HR 2.03, p<0.04), PSA >20ng/ml (HR 2.45, p<0.05) and no neoadjuvant hormone therapy (HR 2.16, p<0.05) were significant prognostic factors. The patients were stratified into a good-risk group (0 or 1 risk factor), intermediate-risk group (2 risk factors), and poor-risk group (3 risk factors). There were significant differences in the BCR free survival among the groups; p<0.01 for low- vs. intermediate-risk group, and p<0.01 for intermediate- vs. high-risk group. The 5- or 10-year BCR free survivals rates were 92.4%, 83.1%, and 75.3%, 72.5%, and 26.7%, 26.7% in good-, intermediate-, and poor-risk patients, respectively. CONCLUSIONS These results indicate that grade group 5, cT3, PSA >20ng/ml and no neoadjuvant hormone therapy were independent risk factors for the BCR in patients with high-risk PCa treated with LDR. The combination of these factors may be helpful to identify candidates for additional treatments to control disease progression. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e280 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Yu Ozawa More articles by this author Masanori Hasegawa More articles by this author Noriaki Santo More articles by this author Yasuto Yagi More articles by this author Toru Nishiyama More articles by this author Ryo Yabusaki More articles by this author Keisuke Aoki More articles by this author Ken Nakamura More articles by this author Choichiro Ozu More articles by this author Kazuhito Toya More articles by this author Masanori Yorozu More articles by this author Shiro Saito More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Results of a phase II trial of neoadjuvant abiraterone + prednisone+ enzalutamide + leuprolide (APEL) versus enzalutamide + leuprolide (EL) for patients with high-risk localized prostate cancer (PC) undergoing radical prostatectomy (RP).

79 Background: Patients with high-risk PC have an increased risk of recurrence and mortality despite therapy. Abiraterone, a CYP17 inhibitor, and enzalutamide, a next generation anti-androgen, have demonstrated improved overall survival in metastatic PC. In this multicenter randomized phase II trial, we evaluate the impact of second generation hormone therapy on RP pathologic outcomes. Methods: Eligible patients had biopsy Gleason score ≥4+3=7, PSA &gt;20 ng/mL or cT3 disease (by prostate MRI). Lymph node were require to be &lt;20 mm. Patients were randomized 2:1 to APE:EL for 6 cycles (24 weeks) followed by RP. All RPs underwent central pathology review. The primary endpoint was the rate of pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm). Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, and safety. Results: 75 patients were enrolled at four sites: DFCI/BWH (n=55), BIDMC (n=11), UW (n=5), JHU (n=4). Median age was 62 years. Most patients had NCCN high-risk disease [n=66, 88%; cT3 n=21 (28%), Gleason 8-10 n=59 (79%), PSA &gt;20 ng/mL n=17 (23%)]. All patients completed 6 cycles followed by RP. Median PSA nadir was 0.03 and 0.02 ng/mL and time to nadir was 3.7 and 4.6 months in the APEL and EL arms, respectively. The combined pCR or MRD rate was 30% (n=15/50) in the APEL arm and 16% (n=4/25) in the EL arm. The response difference was 14% (80% CI -3%-30%, p=0.263). 15 patients (14 in APEL; 1 in EL) had grade 3 adverse events (AEs). The most common grade 3 AEs were hypertension (n=7) and ALT increase (n=5). No grade 4-5 AEs occurred. Conclusions: Neoadjuvant hormone therapy plus RP in men with high-risk PC resulted in favorable pathologic responses (≤5 mm residual tumor) in 16-30% with a trend towards improved pathologic outcomes with APEL and acceptable safety profile. Follow-up is necessary to evaluate the impact of therapy on recurrence rates. Clinical trial information: NCT02268175. [Table: see text]

Abstract PD5-03: TransNEOS: Validation of the oncotype DX recurrence score (RS) testing core needle biopsy samples from NEOS as predictor of clinical response to neoadjuvant endocrine therapy for postmenopausal estrogen receptor positive (ER+), HER2 negative (HER2-) breast cancer patients

Abstract Background: Neoadjuvant therapy for locally advanced breast cancer has the potential to improve surgical therapeutic outcomes without sacrificing the survival advantages of adjuvant therapy. However, determining whether ER+ patients (pts) will respond to neoadjuvant (NA) chemotherapy (CT) or hormone therapy (HT) can be difficult. Not all ER+ pts respond to NACT, while response to NAHT can vary across ER+ pts. Thus, the ability to select pts more likely to benefit from NAHT would represent progress in clinical management of breast cancer. NEOS is a randomized phase III study assessinglong-term prognosis of ER+ primary breast cancer with/without adjuvant CT following NAHT (UMIN 000001090, http://www.umin.ac.jp/). We used archived core biopsy tumor samples from the NEOS study to validate the RS result as a predictor of clinical response and its association with successful breast conserving surgery (BCS) in pts treated with 6 months of NAHT. Methods: NEOS enrolled 904 postmenopausal pts with ER+, HER2-, clinically node negative (cN0) breast cancer to evaluate whether adjuvant CT was necessary for pts who responded to NAHT. In this current study, we enrolled pts with tumors ≥2cm from the NEOS study. Biopsy samples of 333 pts were assessed for the Oncotype DX assay. Response to NAHT was recorded as complete/partial response (CR/PR), or stable/progressive disease (SD/PD). Primary endpoint of this study was to evaluate clinical response (CR/PR) to NA letrozole between pts with low (&amp;lt;18) and high (≥31) RS result. Secondary endpoints include evaluating the relationships between clinical response and continuous RS results, and other covariates including age, tumor size, grade, Ki67 by IHC, ER and PR single gene scores, and ER and proliferation gene group scores by RT-PCR. Results: The analysis included 294 pts with median age of 63 yrs, median tumor size of 25mm, and 66% were nuclear grade 1. 156 (53.0%), 83 (28.6%) and 54(18.4%) cases were low, intermediate, and high RS groups by Oncotype DX, respectively. Six (2%), 126 (42.8%), 149 (50.3%), 13 (4.4%) cases experienced CR, PR, SD, PD as clinical response, respectively, similar to that of all NEOS pts. Clinical response rate was 54%, 42% and 22% in low, intermediate, and high RS groups, respectively. The proportion of pts with clinical response was significantly higher in the low RS group vs the high RS group (p&amp;lt;0.001). In univariate analyses, continuous RS was significantly associated with clinical response (p&amp;lt;0.001), along with ER (p=.02), PR (p&amp;lt;0.001), and ER gene group score (p&amp;lt;0.001). Other covariates were not associated with clinical response. Conclusion: The Oncotype DX RS test in core biopsy samples is validated as a predictive assay for clinical response of NAHT in postmenopausal, ER+/HER2-, cN0, primary early breast cancer pts. Further results on the association of RS results with BCS outcomes following NAHT will be presented. These results when combined with previously published data on RS in NACT studies help guide pts with ER+, HER2- breast cancer with NAHT vs NACT treatment options to maximize clinical response. Citation Format: Yamamoto Y, Iwata H, Masuda N, Fujisawa T, Toyama T, Kashiwaba M, Ohtani S, Taira N, Sakai T, Hasegawa Y, Nakamura R, Akabane H, Shibahara Y, Sasano H, Yamaguchi T, Sakamaki K, Chao C, McCullough D, Sugiyama N, Ohashi Y. TransNEOS: Validation of the oncotype DX recurrence score (RS) testing core needle biopsy samples from NEOS as predictor of clinical response to neoadjuvant endocrine therapy for postmenopausal estrogen receptor positive (ER+), HER2 negative (HER2-) breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-03.

Abstract P2-12-11: Does conservative surgery treatment for locally advanced breast cancer safe after neoadjuvant treatment?

Abstract BACKGROUND: The aim of this study was to assess the oncological efficacy of breast conserving surgery (BCS) after neoadjuvant chemotherapy in patients with local advanced breast cancer. PATIENTS AND METHODS: A retrospective cohort study was conducted with locally advanced breast cancer invasive (Stage IIb to III) treated at ICESP, an oncologic referral center between 2008 and 2016. Endpoints were disease free survival (DFS), local disease free survival (LDFS) and overall survival (OS). Multivariable analyses were performed using Cox proportional hazards models. RESULTS: 530 patients were included, 26% (138) were stage IIB, 41.9% (222) IIIA, 29.6% (157) IIIB and 2.5% (13) IIIA. 88.8% (470) were invasive ductal carcinoma. The mean age was 51.5(23-95). 95.5% and 4.5% were submitted Neoadjuvant Chemotherapy and Hormone therapy, respectively. The BCS were performed in 24.5% (130) patients versus 75.5% (400) of mastectomies. The mean follow up was 36.4(0.16-80.2) months. There were no differences in local disease free-survival 59 (95%CI 58-61) versus 60 (95%CI 57-60); p=0.4 and overall survival 56.2 (95%CI 52-60) versus 59.3(95%CI 53-65); p= 0.24 for mastectomy and BCS. The disease free survival was lower at mastectomy group 51.4 (95%CI 49-53) versus 56,8 (95%CI 53-59); p=0.01. Logistic regression models were significant only for cancer stage both patterns, although the results were better for masses, particularly when kinetic assessments were included (LR 12.8; p = 0.005) CONCLUSION: In our population, the BCS does not affect the overall and local disease-free survival rates, which seems to be safe to perform in patients who desire to conserve the breast after neoadjuvant treatment. Citation Format: Boufelli G, Mota BS, Franca FC, Doria MT, Maesaka JY, Ricci MD, Piato JRM, Rocha FBC, Giribela AHG, Gonçalves R, Masili-Oku S, Mano MS, Chala LF, Thompson BM, Baracat EC, Filassi JR. Does conservative surgery treatment for locally advanced breast cancer safe after neoadjuvant treatment? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-11.

Human epidermal growth factor receptor 2 dual blockade with trastuzumab and pertuzumab in real life: Italian clinical practice versus the CLEOPATRA trial results

ObjectivesGiven their inclusion and exclusion criteria, randomized clinical trials (RCT) might not include a population that truly mirrors real life (RL). This raises concerns about the applicability of RCT results in clinical practice. We evaluated the efficacy of anti-HER2 treatment with pertuzumab combined with trastuzumab and a taxane as first-line treatment for HER2-positive metastatic breast cancer in a RL setting, and compared the safety results obtained in our population versus the experimental cohort of the CLEOPATRA RCT, which led to the approval of this therapy. Materials and methodsPatients treated with trastuzumab, pertuzumab and a taxane were enrolled in this retrospective study. We compared the tumor features and the patients' characteristics of the RL cohort to those of the CLEOPATRA cohort. We also compared the median progression-free survival (PFS) in the RL population versus specific patients' subgroups. ResultsRL patients were more frequently HR-positive, less likely to have visceral metastases (P < .001 for both) and had more frequently received (neo)adjuvant hormone therapy or trastuzumab than CLEOPATRA patients (P = .004 and P < .001, respectively). The median number of anti-HER2 cycles was 8 vs 24 and the median number of cycles was 7 vs 8 for docetaxel in the RL versus CLEOPATRA population, respectively. Adverse reactions of all grades were less frequent in RL. Median PFS was 27.8 months in the RL population and the treatment was equally effective in all patients' subgroups. ConclusionThis study provides compelling evidence that pertuzumab, trastuzumab and a taxane are effective and safe also in a clinical scenario.

Prediction of organ-confined disease after robot-assisted radical prostatectomy in patients with clinically locally-advanced prostate cancer

Little is known about the preoperative predictive factors that could identify subsets of favorable patients who can be possibly cured with robot-assisted radical prostatectomy (RARP) alone in locally advanced prostate cancer (LAPCa). Our study was designed to identify clinical predictors of pathologic organ-confined disease (pOCD) in RARP setting. Between 2007 and 2013, clinicopathological and oncological data from 273 consecutive men undergoing robot-assisted RP with extended PLND for clinically LAPCa were reviewed in a single-institution, retrospectively. After exclusion of patients who received neoadjuvant hormone treatment before surgery, 186 subjects satisfied the final inclusion criteria. Fourty-three patients (23.1% of total cohort) with preoperative clinically LAPCa patients were down-staged to pOCD following RARP. Preoperative prostate-specific antigen (PSA) level, preoperative PSAD, positive core percent, maximal tumor volume in any core, and biopsy Gleason score were significantly associated with down-staging into pOCD following RARP. Multivariate logistic regression analysis revealed that lower preoperative PSA (≤10ng/mL) and maximal tumor volume in any core (≤70%) were independent predictors of pOCD following RARP. Approximately 23% of preoperative clinically LAPCa patients were down-staged to pOCD following RARP. Preoperative PSA and maximal tumor volume in any biopsy core might be useful clinical predictors of pOCD in clinically LAPCa patients in RARP setting.

Post prostatectomy outcomes of patients with high-risk prostate cancer treated with neoadjuvant androgen blockade.

Patients with high-risk prostate cancer have an increased likelihood of experiencing a relapse following radical prostatectomy (RP). We previously conducted three neoadjuvant androgen-deprivation therapy (ADT) trials prior to RP in unfavorable intermediate and high-risk disease. In this analysis, we report on the post-RP outcomes of a subset of patients enrolled on these studies. We conducted a pooled analysis of patients with available follow-up data treated on three neoadjuvant trials at three institutions. All patients received intense ADT prior to RP. The primary endpoint was time to biochemical recurrence (BCR). BCR was defined as a PSA ≥ 0.2 ng/mL or treatment with radiation or androgen-deprivation therapy for a rising PSA < 0.2 ng/mL. Overall, 72 patients were included of whom the majority had a Gleason score ≥ 8 (n = 46, 63.9%). Following neoadjuvant therapy, 55.7% of patients (n = 39/70) had pT3 disease, 40% (n = 28) had seminal vesicle invasion, 12.9% (n = 9) had positive margins, and 11.4% (n = 8) had lymph node involvement. Overall, 11 (15.7%) had tumor measuring ≤ 0.5 cm, which included four patients (5.7%) with a pathologic complete response and seven (10.0%) with residual tumor measuring 0.1-0.5 cm. Compared to pretreatment clinical staging, 10 patients (14.3%) had pathologic T downstaging at RP. The median follow-up was 3.4 years. Overall, the 3-year BCR-free rate was 70% (95% CI 57%, 90%). Of the 15 patients with either residual tumor ≤ 0.5 cm or pathologic T downstaging, no patient experienced a recurrence. In this exploratory pooled clinical trials analysis, we highlight that neoadjuvant therapy prior to RP in unfavorable intermediate and high-risk patients may potentially have a positive impact on recurrence rates. Larger studies with longer follow-up periods are warranted to evaluate the impact of neoadjuvant hormone therapy on pathologic and long-term outcomes.