bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole blood androgen receptor (AR) variant (ARV12, ARV14) expression and overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Giridhar Karthik , Sosa Carlos , Hillman David W. , Sanhueza Cristobal T. , Wang Liguo , Cheville John C. , Dehm Scott , Kohli Manish
Published: September 2018

5058

Background: The detection of full length AR (AR-FL) or AR variants (AR-Vs) in blood and association with outcomes in mCRPC is unknown. We compared whole blood mRNA expression of AR-FL and AR-Vs to circulating tumor cells (CTCs) for predicting OS and time to treatment failure (TTF). Methods: We isolated RNA from whole blood collected in PAXgene RNA tubes and concurrent metastatic tissue biopsy from 51 men with mCRPC prior to initiation of abiraterone acetate in a prospective clinical trial (NCT#01953640). Whole transcriptome sequencing (RNAseq) was performed on blood samples and paired biopsies to detect AR-FL, ARV1, ARV3, ARV7, ARV8, AR12, ARV14, and ARV45. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. The Pearson correlation coefficient was calculated between AR-FL in blood and matched bone biopsy. CTCs were determined using the CELLSEARCH assay. Cox proportional hazard regression analysis was performed on AR-FL, each AR-V, and CTCs for association with OS and TTF. We compared the area under the curve (AUC) using CTCs alone to a multivariable model that included AR-Vs for predicting OS. Results: The median follow up was 3.0 years, (range 0.3-3.5); the median CTC count was 3 (range 0-372); 34/53 men were deceased. Blood based AR-FL or AR-Vs were detected in 50/53 patients with following distribution: AR-FL (41/53), ARV3 (9/53), ARV45 (8/53), ARV12 (4/53), ARV14 (4/53), ARV7 (2/53), and ARV8 (2/53). Whole blood AR-FL transcripts were highly correlated to paired bone biopsy (r2= 0.76). Elevated transcripts of either ARV12 or ARV14 were associated with decreased OS [hazard ratio (HR) 3.46, p = 0.006]. CTC count ≥5 was associated with poorer OS [HR 3.42, p = 0.02] and shorter TTF [HR 3.52, p = < 0.001]. Adjusting for CTC counts, in a multivariate model, blood AR12 expression was associated with poor OS [HR = 6.33, p = 0.009]. AR12 and CTCs trended toward improved AUC compared to CTC alone (0.78 vs 0.71, p = 0.07). Conclusions: AR-FL and AR-Vs are detectable in whole blood and are highly correlated with metastatic bone AR-FL expression. AR-Vs may add to prognostication in mCRPC and further validation is needed. Clinical trial information: NCT#01953640.
Ten-year overall and prostate cancer (PCa)-specific mortality in high-risk patients after high-dose-rate brachytherapy combined with external beam radiation therapy (HDR-BT/EBRT) compared with EBRT alone.
Authors: Wedde Trude Baastad , Fosså Sophie , Brabrand Sigmund , Kaasa Stein , Russnes Kjell Magne , Hellebust Taran Poulsen , Tafjord Gunnar , Lilleby Wolfgang
Published: September 2018

5059

Background: The effect of dose-escalation with HDR-BT boost for high-risk PCa is not known. The objective is to compare 10-year PCa-specific mortality (PCSM) and overall mortality (OM) in non-metastatic patients treated with HDR-BT/EBRT (2004-2010) to EBRT alone (historical RCT, SPCG-7, 1996-2003). Methods: HDR-BT boosts (10 Gy x 2) were given 2 weeks apart followed by 50 Gy conformal EBRT (2 Gy x 25) to the prostate and seminal vesicles (assuming alpha/beta ratio of 3, EQD2 = 102 Gy). The HDR-BT/EBRT group (N:325) received Androgen Deprivation Therapy (ADT) for a total of 2 years. Patients in the control group (N:296) received 70 Gy (2Gy x 35) to the prostate and seminal vesicles with lifelong Anti-Androgen Treatment (AA). cT1-cT2 vs cT3 tumours and Gleason score 6-7 vs 8-10 were analysed. For each treatment group PCSM and OM were established by Kaplan-Meier (KM) analyses, and inter-treatment differences were tested by the logrank tests. Cox regression analysis evaluated the significance of available pre-treatment variables. Significance level p < 0.05. Results: In both groups the median age was 66 years. Median follow-up was 104 (range 13-120) and 120 (range 3-120) months for the HDR-BT/EBRT and EBRT groups respectively. KM plots revealed an 1.8% risk of PCSM in the HDR-BT/EBRT patient group and an 8.4% risk in the EBRT cohort (p = 0.001). For OM, the figures were 12.3% in the HDR-BT/EBRT group compared to 23.3% in the EBRT group (p = 0.014). In the Cox regression analysis, treatment (HR = 3.9, CI95% 1.8-8.3) and Gleason score (HR = 3.2, CI95% 1.8-5.9) were significantly associated with PCSM whilst T-stage, age and PSA levels were not. Treatment (HR = 1.7, CI95% = 1.1-2.6) was the only factor significantly associated with OM. Conclusions: In men with high-risk PCa dose-escalation with HDR-BT/EBRT compared to EBRT alone resulted in a significantly decreased risk of 10-year PCSM and OM despite shorter length of hormonal therapy. PCSM was significantly influenced by both Gleason score and type of treatment, whereas treatment remained the only significant covariate for OM.
P53 status in primary tumor predicts efficacy of first-line abiraterone and enzalutamide in castration-resistant prostate cancer patients.
Authors: Maughan Benjamin Louis , Guedes Liana , Boucher Kenneth M. , Rajoria Gaurav , Liu Zach , Klimek Szczepan , Zoino Roberto , Antonarakis Emmanuel S. , Lotan Tamara L.
Published: September 2018

5064

Background: We tested whether tissue-based analysis of p53 and PTEN genomic status, measured predominantly in primary tumor samples, may be predictive for sensitivity to abiraterone and enzalutamide in castration resistant prostate cancer (CRPC). Methods: We performed a retrospective analysis of 309 consecutive patients with CRPC treated with first-line abiraterone or enzalutamide. Of these, 116 men (38%) had available tumor tissue for analysis, and formed the basis of this study. Deleterious TP53 missense mutations and PTEN deletions were interrogated using genetically validated immunohistochemical assays for p53 protein nuclear accumulation and PTEN protein loss. OS and PFS were compared between patients with and without p53 and/or PTEN alterations. Results: 46% of evaluable cases had PTEN loss and 27% had p53 nuclear accumulation. 45% (53/118) of cases underwent targeted next generation sequencing and p53 nuclear accumulation was 91% sensitive and 90% specific for underlying TP53 missense mutation. OS and PFS did not differ significantly according to PTEN status but were associated with p53 status. Median OS was 15.8 months (95% CI, 15.8–23.9) and 28.7 months (95% CI, 28.7–42.7) for men with and without p53 nuclear accumulation, respectively (HR 1.98; P = 0.007). Median PFS was 5.5 months (95% CI, 3.53–10.5 months) and 10.2 months (95% CI, 7.37–13.3 months) in men with and without p53 nuclear accumulation, respectively (HR 1.73; P = 0.013). In multivariable analyses, p53 status was independently associated with both OS (HR 2.13; P = 0.016) and PFS (HR 1.83; P = 0.034). This effect was also seen in the subset of patients with prostatectomy tissue only. In patients with p53 nuclear accumulation median PFS (p < 0.001) and median OS (p < 0.001) were decreased compared to wild-type patients. No effect was seen with PTEN loss in either PFS (p = 0.12) or OS (p = 0.50). Conclusions: p53 status may be a biomarker of sensitivity to novel hormonal therapies in CRPC. PTEN was not a biomarker of sensitivity in our study. These results require prospective validation.
History of PSA screening on prostate cancer aggressiveness.
Authors: Cullen Jennifer , Gerald Thomas , Burke Allen , Kuo Huai-Ching , Rosner Inger L. , Srivastava Shiv , Sesterhenn Isabell
Published: September 2018

5066

Background: In 2012, PSA screening for prostate cancer (CaP) detection was given a “Grade D” recommendation for all men by the USPSTF. Recent U.S. studies report declines in PSA screening with concomitant increases in advanced CaP at diagnosis. This study examined the association between PSA screening history and CaP aggressiveness in a racially diverse, military cohort with equal health care access. Methods: This retrospective cohort study evaluated CaP patients undergoing radical prostatectomy (RP) from 1994-2015 at Walter Reed National Military Medical Center. Whole-mounted prostatectomy specimens were classified using 2014 ISUP Gleason grading system. Excluding the diagnostic PSA, screening history was categorized as: ≥ 6 PSA’s prior to CaP diagnosis (uppermost quartile), 1-5 (lower 3 quartiles), vs. no screening history. Multivariable logistic regression (MLR) was used to examine NCCN risk stratum (intermediate-high vs. low) and Gleason upgrade (GU) from biopsy to RP. Multivariable Cox proportional hazards (Cox PH) analyses were used to model time to biochemical recurrence (BCR). Multivariable models controlled for age at RP, race, family history and obesity (BMI > 30 vs. ≤ 30 kg/m2). The GU and BCR models also controlled for NCCN risk classification. Results: There were 1,772 eligible patients with a median follow-up and age at RP of 7.0 and 59.8 years, respectively. Prior to CaP diagnosis, 42% and 19% of men had 1-5 and ≥ 6 PSA’s screenings, respectively. MLR showed greater odds of intermediate or high vs. low risk disease for PSA screening history of none vs. 1-5 (OR = 1.33, CI = 1.03-1.70, p = 0.028) but not for none vs. ≥ 6 (p = 0.44). MLR showed increased odds of GU for none vs. ≥ 6 (OR = 1.81, CI = 1.23-2.7, p < 0.001). Multivariable Cox PH models showed incrementally poorer BCR-free survival as screening history decreased (HRNone vs. ≥6 = 2.27, CI = 1.54-3.33, p < 0.001; HRNone vs. 1-5= 1.49, CI = 1.15-1.92, p = 0.002). Conclusions: In this RP cohort, higher risk stratum, increased GU, and poorer BCR-free survival were associated with no PSA screening history. BCR-free survival was incrementally worsened by less PSA screening. A complete absence of PSA screening may lead to more aggressive disease at presentation and poorer clinical outcomes.
Validation of cAMP phosphodiesterase-4D7 (PDE4D7) for its independent contribution to risk stratification in a prostate cancer patient cohort with longitudinal biological outcomes.
Authors: Rijntjes Jos , Alves de Inda Marcia , van Strijp Dianne , den Biezen-Timmermans Eveline , van Brussel Anne , Wrobel Janneke , van Zon Hans , Vos Pieter , Baillie George S , Tennstedt Pierre , Schlomm Thorsten , Houslay Miles , Bangma Chris H. , Heinzer Hans , Hoffmann Ralf
Published: September 2018

5069

Background: In this study we present the retrospective validation of the prognostic prostate cancer biomarker PDE4D7 in predicting longitudinal biological outcomes in a historical cohort of radical prostatectomy patients. Methods: Biopsy punches from 550 patients were collected from a representative tumor area of FFPE surgical resections. RNA was extracted and PDE4D7 quantified by one-step RT-qPCR. PDE4D7 scores were calculated by normalization of PDE4D7 to the averaged expression of four reference genes. The independent prognostic value of the PDE4D7 scores were evaluated using uni- and multivariate Cox proportional hazard regression. Multivariate analyses were adjusted for clinical prognostic variables. Post-surgical outcomes tested were: PSA relapse, start of salvage treatment, progression to metastases, overall and prostate cancer specific mortality. Logistic regression was used to create a combined prognostic model of PDE4D7 with clinical risk and tested in outcome prediction. Results: The PDE4D7 score was significantly associated with time to PSA failure after prostatectomy (HR 0.53; 95% CI 0.41-0.67 for each unit increase; p < 1.0E-04). After adjustment for pathology Gleason, pT stage, surgical margin status, and seminal vesicle invasion the HR was 0.55 (95% CI 0.43-0.72; p < 1.0E-04). Patients with a high PDE4D7 score that were clinically classified as intermediate to high risk of progression were re-classified into a group with an average progression risk less than the average cohort risk of clinically very low risk patients. The maximum benefit, compared to Gleason score, was observed in the clinically intermediate favorable risk group. Combining clinical risk with PDE4D7 scores improved the overall risk stratification. Conclusions: The PDE4D7 score has potential to provide independent risk information and, in particular, to re-stratify patients with clinical intermediate to high risk characteristics to a very low risk profile.
Development and external validation of a novel risk score to identify insignificant prostate cancer.
Authors: Dutto Lorenzo , Witt Jorn H. , Urbanova Katarina , Wagner Christian , Schuette Andreas , Addali Mustafa , Kelly John D , Nathan Senthil , Briggs Timothy Philip , Sridhar Ashwin , Gori Stefania , Ahmad Amar , Shaw Gregory
Published: September 2018

5073

Background: Active surveillance is increasingly used for insignificant prostate cancer (PCa). In order to identify suitable patients, risk scores have been developed which use pre-operative factors. We evaluated the accuracy of 9 separate tools developed to identify patients harbouring insignificant PCa in 2613 patients who underwent radical prostatectomy for Gleason 3+3 PCa. We have developed and validated a novel risk score to correctly identify insignificant PCa for use in unscreened patient cohorts using non-dichotomised clinical predictors. Methods: 2799 patients who would have been candidates for AS (Gleason score 6 only) patients underwent robotic radical prostatectomy between 2006 and 2016 at a tertiary referral center. The volume and grade of tumour in the resected prostate was analysed. Inignificant PCa was defined as Gleason 3+3 only, index tumour volume <1.3 cm3 , total tumour volume <2.5 cm3 (updated ERSPC definition). 2613 patients were included in the final analysis. We computed the accuracy (specificity, sensitivity and area under the curve (AUC) of the receiver operator characteristic) of 9 predictive tools. Multivariate logistic regression with elastic net regularisation was used to develop a novel tool to predict insignificant prostate cancer using age at diagnosis, baseline PSA, TRUS volume, clinical T-stage, number of positive cores and percentage of positive cores as predictors. This tool was validated in an external cohort of 441 unscreened patients undergoing surgery for Gleason 6 PCa. Results: All of the predefined tools rated poorly as predictors of insignificant disease as none of them reached the required AUC threshold of 0.7. The new tool performed well in training and validation cohorts. Conclusions: Pre-existing predictive tools to identify indolent PCa have a poor predictive value when applied to an unscreened cohort of patients. Our novel tool shows good predictive power for insignificant PCa in this population in training and validation cohorts. The inherent selection bias due to analysis of a surgical cohort is acknowledged. [Table: see text]
Association of risk of clinical recurrence (CR) and prostate cancer death (PCD) with a 17-gene genomic prostate score (GPS) value <20.
Authors: Febbo Phillip G. , Crager Michael , Burke Emily , Lawrence H. Jeffrey , Cullen Jennifer , Klein Eric A.
Published: September 2018

5074

Background: Over-treatment of localized prostate cancer (PC) can result from over-estimation of a patient’s risk of CR and PCD. GPS (scale 0-100) has been validated to predict adverse pathology, biochemical recurrence, metastasis, and PCD and provides a more accurate overall assessment of patient risk than clinical risk factors alone. A recent validation study found that no patients with AUA Low- or Intermediate-risk disease and a GPS of <20 developed PC metastases or PCD. Here, 2 large longitudinal PC cohorts were analyzed to estimate the risk of CR and PCD for GPS 20 units. Methods: Data from Klein et al. European Urology (EU) 2014 and Cullen et al. EU 2014 were analyzed to establish the risk of CR and PCD associated with a pre-established GPS cut-point of 20. Patients were divided based on the value of GPS (≤20, >20). Cox regression analyses accounted for cohort sampling weights. Since GPS was developed using Klein et al, standardized hazard ratios (std HR, HR for 1 SD change in the covariate) for GPS and CR and PCD survival curves for the 2 groups were estimated correcting for regression to the mean (RM). Results: Of the 402 patients in Cullen et al. (median follow up 5.2 years), only 5 patients developed metastases; all 5 had GPS >20. For Klein et al., of 426 patients with a median follow up of 6.6 years, there were 109 CR (metastasis and local recurrence) and 39 PCD; only one patient with events had a GPS <20. Overall 28% of patients had GPS <20. GPS was a significant predictor for both CR (std HR 2.50 (95%CI 1.99, 3.15, p <0.001, RM-corrected std HR 2.16, FDR <0.1%) and PCD (std HR 2.90 (95% CI 2.06,4.06, p<0.001, RM-corrected std HR 1.96, FDR <0.1%) after adjustment for AUA group. Men with intermediate risk prostate cancer and a GPS score of < 20 have a 2.6% and 0.7% 10-year RM-corrected risk of CR and PCD, respectively (Table 1). Conclusions: GPS strongly predicts risk of CR and PCD in men with AUA Low- or Intermediate-risk PC. Patients with a GPS score <20 have a very low risk of CR or PCD and should be considered for AS. [Table: see text]
Long-term results of a prospective phase II study of androgen deprivation therapy, external radiation, cs-131 brachytherapy, and adjuvant docetaxel in high-risk prostate cancer.
Authors: Rice Stephanie , Le Gloribel K , Hussain Arif , Mannuel Heather Dorothy , Naslund Michael K , Amin Pradip P. , Kwok Young
Published: September 2018

5079

Background: We report the long-term results of a prospective, Phase II study of 2 years androgen deprivation therapy (ADT), 45 Gy bone marrow sparing pelvic radiation (BMS-PR), Cs-131 brachytherapy boost (85 Gy), and 4 cycles of adjuvant docetaxel (75 mg/m2 q21d + prednisone) in high risk, localized prostate cancer. Methods: From2006-2014,38 patients were enrolled. Acute hematologic as well as acute and chronic gastrointestinal (GI) and genitourinary (GU) toxicities were scored based on the CTCAE v3.0 criteria. Biochemical recurrence was defined as a nadir + 2 rise in PSA. Actuarial freedom from PSA failure (bNED) and overall survival (OS) were calculated using SPSS v24. Median Gleason score was 8 (74% Gleason 8-10). Median PSA was 11.2 (range 2.8-96). Results: A total of 38 patients were enrolled on the trial. Median age was 62 years (range 45-82). 82% of patients completed all protocol specified treatments, while 84% completed all 4 cycles of docetaxel. After a median follow up of 44 mo (range 3.4-118), the 5-year bNED rate was 86% while 5-year OS was 80%. Acute grade ≥ 2 GI and GU toxicity rates were 12.5% and 21.9%, respectively. Chronic grade ≥ 2 GI and GU toxicity rates were 3.1% and 3.1%, respectively. 25.6% (n = 10) patients receiving docetaxel developed grade 4 hematologic toxicity. There were no grade 5 toxicities. Conclusions: We found this aggressive multi-modal approach to be feasible, safe, well-tolerated, and effective. It does not appear that BMS-PR decreases hematologic toxicity. Cs-131, with its 9.7 day half-life, does not appear to increase acute or late toxicity. These data build upon the ASCENDE-RT and RTOG 0521 trials that demonstrate the added benefits of brachytherapy boost and adjuvant docetaxel, respectively, in high-risk prostate cancer.
Mastectomy rates in relation to adoption of a margin guideline.
Authors: Morrow Monica , Katz Steven J. , Jagsi Reshma
Published: September 2018

508

Background: Surgery after initial lumpectomy to obtain a bigger negative margin is common and may lead to mastectomy. The impact of a 2014 consensus statement endorsing a minimal negative margin for invasive breast cancer on surgeon attitudes, re-excision rates, and final surgical procedure is uncertain. Methods: Women with stage I and II breast cancer diagnosed between 7/13–8/15 and reported to the Los Angeles and Detroit SEER registries were surveyed about 2 months post diagnosis, and 70% responded; 3729 comprise the analytic sample. All attending surgeons identified by the patients (n=489) were sent a questionnaire at the end of the patient survey period, and 376 (77%) responded. Pathology reports were reviewed for margin status. Multinomial regression models were used to assess trends. Results: The 67% initial lumpectomy rate was unchanged during the study. The final lumpectomy rate increased by 13% (to 65% from 52%) from 2013–2015, accompanied by a decrease in unilateral (to 18% from 27%) and bilateral (to 16% from 21%) mastectomy (p=0.002). Surgery after lumpectomy, both re-excision and mastectomy, declined by 16% (p<0.001). Pathology review showed no association between date of treatment and positive margins. Patient report of surgeon-recommended mastectomy after initial lumpectomy declined to 8% from 20% (p<0.001). 69% of surgeons endorsed a margin of no ink on tumor to avoid re-excision in ER+PR+ cancer and 63% for ER-PR- cancer. Surgeons treating >50 breast cancers annually were more likely to accept this margin than those treating <20 cases (p<0.001). Conclusions: Additional surgery after initial lumpectomy markedly decreased between 2013‒2015 after publication of a margin guideline endorsinga minimal negative margin. This resulted in a substantial increase in lumpectomy as the definitive surgical procedure, which illustrates that guidelines can be an effective, low-cost approach to addressing clinical controversies.
Prostate cancer (PCa) in 696 hypogonadal men with and without long-term testosterone therapy (TTh): Results from a controlled registry study.
Authors: Haider Ahmad , Haider Karim Sultan
Published: September 2018

5085

Background: There is no evidence that TTh in men with hypogonadism increases PCa incidence or severity. A Canadian group recently found that long-term TTh decreased the risk of PCa diagnosis (Wallis et al., Lancet Diab Endocrinol 2016; 4:498). We assessed incidence and severity of PCa in hypogonadal men on long-term TTh (T-group) in comparison to an untreated hypogonadal control group (CTRL). Methods: 400 men with testosterone ≤350 ng/dL and symptoms received testosterone undecanoate 1000 mg every 3 months for up to 10 years. 296 hypogonadal men (57-74) opted against TTh. Median follow-up: 8 years. Total observation time covered more than 5,000 patient-years. Prostate volume (PV), PSA, weight and C-reactive protein (CRP) were measured and digital rectal examination/transrectal ultrasound performed before treatment initiation and then every 6-12 months. Biopsies were performed when indicated according to EAU guidelines. Results: In the T-group, PV increased slightly but significantly by 2.41 mL (p < 0.0001), PSA by 0.22 (NS). In CTRL, PV decreased slightly but significantly by -1.20 mL (p < 0.005), PSA by -0.38 (p < 0.0001). Weight dropped by 18.23% in the T-group and increased by 1.78% in CTRL, CRP decreased significantly in the T-group and remained unchanged in CTRL. In the T-group, 9 men (2.3%) were diagnosed with PCa. In CTRL, 15 (5.1%) were diagnosed with PCa. The incidence per 10,000 years was 29 in the T-group and 102 in CTRL. The mean baseline age of PCa patients was 65 years in the T-group and 65.5 in CTRL. Prostatectomy was performed in all men. In the T-group, all but 1 patient had a Gleason score ≤6, and all a predominant Gleason score of 3. Tumor grade was G2 in all 9 (100%), tumor stage T2a in 7 (78%) and T2b in 2 (22%) patients. In CTRL, Gleason score was > 6 in all 15 patients. 4 men had a predominant Gleason score of 3, 10 had 4, and 1 had 5. Tumor grade was G2 in 7 (46.7%) and G3 in 8 (53.3%) patients, tumor stage T2b in 1 (6.7%), T2c in 1 (6.7%), T3a in 1 (6.7%), T3b in 7 (46.7%) and T3c in 6 (50%) patients. Conclusions: In hypogonadal men, TTh may decrease PCa incidence compared to CTRL. PCa was less severe in the T-group. Weight loss and reduced inflammation by TTh may have contributed to our findings.
COOLHAIR: A prospective randomized trial to investigate the efficacy and tolerability of scalp cooling in patients undergoing neoadjuvant chemotherapy for early breast cancer.
Authors: Smetanay Katharina , Junio Philippe , Feißt Manuel , Hassel Jessica Cecile , Mayer Luisa , Matthies Lina Maria , Schumann Arina , Hennigs André , Heil Joerg , Sohn Christof , Jaeger Dirk , Schneeweiss Andreas , Marme Frederik
Published: September 2018

525

Background: Chemotherapy induced alopecia (CIA) is a distressing side effect for women with breast cancer (BC) undergoing chemotherapy (CT). Scalp cooling is a method aiming to prevent CIA, but its efficacy is not well defined. Observational studies show a positive effect of scalp cooling to reduce hair loss, but randomized trials until recently have been lacking. Methods: In our monocentric prospective randomized trial patients with early BC undergoing (neo)adjuvant CT were 1:1 randomized to either scalp cooling (CAP) or not (noCAP). All patients received 18 to 24 weeks of anthracycline (A) and/or taxane (T)-based CT. The DigniCap System was used for scalp cooling. The primary endpoint was patient reported rate of alopecia according to the Dean Scale (Grade 0: no hair loss, grade 1: > 0 - 25%; grade 2: > 25 - 50%; grade 3: > 50 - 75%; grade 4: > 75%). Hair preservation was defined as hair loss £ grade 2. Secondary endpoints were rate of alopecia determined by nursing staff and an independent and blinded evaluator, rate of wig/scarf use as well as quality of life. Results: From August 2014 until January 2016 seventy-nine patients were included (41 CAP and 38 noCAP). The drop-out rate was 32% in the CAP arm and 34% in the noCAP arm. Main reasons for drop out were hair loss, adverse events (CAP) and randomization into control arm. At the time of this analysis all patients had completed CT. Hair preservation was observed in 39% of patients in the CAP arm versus 0% in the No CAP arm (p < 0.001). There was a strong concordance between patients and staff evaluation (weighted Cohen's Kappa = 0.92). Wig/scarf use was significantly less frequent in the CAP group (36% vs 92% at home, p < 0.001; 64% vs 91% outside, p < 0.001). We did not observe any differences in hair preservation between A-based and non A-based regimens. Conclusions: Our prospective randomized trial shows that scalp cooling is effective in preventing CIA in a relevant number of patients. This option should be made available for patients undergoing T+/-A-based (neo)adjuvant chemotherapy for EBC.
Yoga in women undergoing treatment for breast cancer: Impact on quality of life in a randomized controlled trial.
Authors: Nair Nita S. , Goel Nishu Singh , Hawaldar Rohini W , Siddique Shabina , Parmar Vani , Pandey Aarti , Badwe Rajendra A.
Published: September 2018

527

Background: Yoga has been tested in multiple small-randomized studies for its impact on quality of life (QOL) on breast cancer (BC). We propose to study the effect of yoga on disease free survival as the primary endpoint in women with operable breast cancer. (Study methodology details refer to NCT02161900). Methods: Women with non-metastatic BC were randomized to yoga and conventional exercise (YCE) versus conventional exercise only (CE) in addition to standard therapy. Over and above documentation of recurrence and death, QOL was assessed in these women using the EORTC QLQC30, BR23, Brief fatigue inventory (BFI), Visual pain scores (VPS) and a spirituality questionnaire (SQ). EORTC QLQ was assessed at baseline (BL), 6-9 months (mo), 18-21 mo. BFI and VPS at BL, 6-8 mo and 12-15 mo and SQ at BL and 12-15 mo. We report the first interim analysis of QOL in 605 patients randomized to the study with atleast 1 year of follow up. The groups were balanced in both arms with respect to clinico-pathological factors. Results: At 6-9 mo (completion of adjuvant therapy), there was no significant difference in global QOL scores (p = 0.08), however 52% women on YCE showed an improvement from baseline compared to 42% in CE. At 18-21 mo emotional function scores were better in YCE (p = 0.002); with lesser systemic side effects in YCE arm (44% vs 56% p = NS). The median score of fatigue after adjuvant therapy measured by QLQ C30 was lower in YCE (17.37vs22.22, p = 0.003) which was similar to that observed by BFI at 12-15 mo (1.6vs 2, p = 0.04). Also in YCE there was lower reporting of detriment in general activity (41%vs 59%) and mood (34%vs66%) (p = NS). In VPS at 12-15mo, the median scores for pain intensity (p = 0.042), pain on movement (p = 0.038), pain on mobilization (p = 0.008) were lower in YCE. Lastly SQ assessed spirituality and showed no difference, but less deterioration compared to baseline scores in YCE. Conclusions: Yoga did not show a significant difference in global QOL but had a major benefit reaching statistical significance in fatigue, emotional score and pain. Yoga is a low-risk, low-cost complementary therapy that may improve compliance to therapy by improving parameters that can affect day-to-day activity in women with breast cancer. Clinical trial information: NCT02161900.
Effects of age, immune landscape, and response to trastuzumab (H) in HER-2 positive (HER2+) breast cancer in NCCTG (Alliance)-N9831.
Authors: Soyano Aixa Elena , Serie Daniel , Mashadi-Hossein Afshin , Warren Sarah , Colon-Otero Gerardo , Knutson Keith L. , Perez Edith A. , Moreno-Aspitia Alvaro , Thompson E Aubrey , Chumsri Saranya
Published: September 2018

530

Background: Therapeutic efficacy of H involves activation of the immune system.Age-dependent progressive deterioration of the immune response is referred as immunosenescence. In HER2+ breast cancer, the effects of aging and the ability of H to activate endogenous anti-tumor immunity is unknown. A previous report from HERA trial showed no significant increase in risk of early recurrence with age (≤ or > 40). We evaluated the long-term outcome of HER2+ patients (pt) related to age and immune landscape. Methods: 1,392 pt from N9831 trial were evaluated. Stromal tumor infiltrating lymphocytes (sTIL) were evaluated in H&E slides. Lymphocyte predominant breast cancer (LPBC) was defined as sTIL ≥ 50%. Molecular TIL (mTIL) and immune subset signatures were evaluated using NanoString research CodeSets. Cox proportional hazard ratio (HR) was used for analysis. Results: There were 1,111 (79.8%) pt > 40 years old (yo) and 281 (20.2%) pt ≤ 40 yo. Younger age was significantly associated with hormone receptor positivity (p 0.00011) and luminal B subtype (p 0.011). With a median follow up of 10.6 years, there was no significant difference in long-term outcome among pt ≤ 40 vs. > 40 yo who received H (HR = 0.88 (0.62-1.24), p = 0.45). Similar findings were observed when age was dichotomized at 50 and 60 yo. While there was no association between sTIL and age, a small but significant increase in mTIL CD45 expression with age (p 0.003) was observed. Similar small increases in cytotoxic cell (p 0.007) and T cell (p 0.015) immune scores were also observed with increasing age. Among pt who received chemotherapy alone, pt > 40 yo with LPBC (n 55) had excellent outcome with 92.4% recurrence free survival (RFS) at 10 years. However, there was no significant difference in RFS among pt ≤ 40 yo with or without LPBC. Conclusions: Among pt treated with H, there was no significant difference in outcome related to age. In contrast to a decline expected from immunosenescence, we observed small but significant increases in mTIL signatures for total lymphocytes, cytotoxic, and T cell subsets. Among patients who received chemotherapy alone, our data suggested that pt > 40 yo with LPBC had excellent prognosis, compared to pt > 40 yo without LPBC.
A population-based analysis of treatment and outcomes in 2,500 metaplastic breast cancer patients.
Authors: Ong Cecilia Tuongquang , Thomas Samantha Marie , Campbell Brittany Morgan , Greenup Rachel Adams , Plichta Jennifer Kay , Rosenberger Laura Horst , Force Jeremy Meyer , Hyslop Terry , Hwang Eun-Sil Shelley , Fayanju Oluwadamilola Motunrayo
Published: September 2018

532

Background: Metaplastic breast cancer (MBC) is a rare, aggressive variant that is often triple negative (TN). Current guidelines recommend use of standard receptor-based treatment for MBC despite evidence of chemoresistance. We sought to compare treatment patterns and outcomes of MBC and non-MBC. Methods: Women age > 18 with stage I-III MBC and non-MBC histology diagnosed from 2010-2013 were identified in the National Cancer Database. Kaplan Meier and multivariate Cox proportional hazards models were used to estimate MBC association with overall survival (OS). Subgroup analyses were conducted for (1) MBC patients only and (2) TN MBC and TN non-MBC patients. Results: 2451 MBC and 568,057 non-MBC patients were included. 70.3% of MBC were TN vs 11.3% of non-MBC (p < 0.001). 19.2% of MBC were luminal (i.e., ER+ and/or PR+, and HER2-). MBC presented with higher clinical T stage (cT4: 5.4% vs 1.8%) and grade (grade 3: 72.1% vs 29.7%) but was less frequently node-positive (19.1% vs 29.7%, all p < 0.001). A higher proportion of MBC patients were treated with mastectomy (59.0% vs 44.9%), axillary dissection (ALND, 35.2% vs 32.2%), and chemotherapy (74.1% vs 43.1%, all p≤0.001). 5-year OS was reduced among MBC vs non-MBC patients for both the entire cohort (72.7% vs 87.5%) and the TN-only analysis (71.1% vs 77.8%, both log-rank p < 0.001). Among MBC cases, TN subtype was not associated with worse OS than the luminal subtype (HR 1.16, p = 0.28). Chemotherapy (HR 0.69, p = 0.004) and/or radiotherapy (HR 0.52, p < 0.001) improved OS in MBC, and the proportional benefit of chemotherapy did not vary with pathological T or N stage (interaction p > 0.05 for both). Among TN patients, a higher proportion of TN MBC patients underwent mastectomy (58.4% vs 49.5%, p < 0.001), but in contrast to the full cohort, a lower proportion of TN MBC patients received chemotherapy (76.6% vs. 78.7%, p = 0.008) and ALND (35.2% vs. 38.2%, p = 0.01) vs TN non-MBC patients. Conclusions: MBC had worse OS vs non-MBC, and unlike other histologies, outcome was not driven by receptor status. Multimodal therapy improved outcomes. Further investigation into MBC tumor biology and the development of MBC-specific guidelines could potentially improve treatment standardization and outcomes.
Prospective study of magnetic resonance imaging (MRI) and multiparameter gene expression assay in ductal carcinoma in situ (DCIS): A trial of the ECOG-ACRIN Cancer Research Group (E4112).
Authors: Khan Seema Ahsan , Gatsonis Constantine , Snyder Brad , Lehman Constance D , Sparano Joseph A. , Solin Lawrence J. , Badve Sunil S. , Corsetti Ralph L , Rahbar Habib , Spell Derrick W , Blankstein Kenneth Bruce , Han LInda K , Sabol Jennifer L. , Bumberry John R , Miller Kathy D. , Comstock Christopher
Published: September 2018

534

Background: Prior retrospective studies have evaluated breast MRI in DCIS, and prospective-retrospective biomarker studies have shown that the DCIS Score is prognostic for recurrence after BCS alone. E4112 is a prospective cohort study designed to assess the combined impact of breast MRI and DCIS Score on surgical and RT management. Methods: Women diagnosed with screen-detected DCIS on core biopsy, if BCS eligible, underwent breast MRI. Those remaining so following MRI and related biopsies, with no invasive disease, underwent BCS. If final surgical margins were ≥2 mm, the DCIS lesion was submitted for DCIS Score assay. Women with low DCIS Score (≤39, LS) were advised that RT could be avoided; RT was recommended to those with high/intermediate (H/I) scores. The primary objective was to estimate the fraction converting to mastectomy (Mx) following MRI. Secondary objectives included estimation of re-operation rates after first BCS, and DCIS Score distribution.A sample size of 333 evaluable women would allow estimation of Mx rate of 12% with 95% confidence interval 9-16%. Results: 334 enrolled women had completed surgery; the first surgical procedure was Mx in 54 (16.2%) and BCS in 280 (83.8%), of whom 62 (22.1%) required at least one re-excision, and 11 (3.9%) converted to Mx. DCIS Scores were obtained on 171 patients who completed BCS, of whom 82 were LS and 89 were H/I. Demographics were similar between the two groups, other features will be reported. Only 7/82 (8.5%) of the LS group received RT, whereas 82/89 (92.1%) of the H/I group received RT. Of the 98 BCS patients who did not qualify for DCIS Score-based therapy, 23 had invasive disease, 34 had final surgical margins < 2 mm, and 13 had both. There was insufficient tissue for DCIS Score in 11, and 17 did not complete follow-up. Conclusions: In this study, among DCIS patients who were BCS-eligible following MRI, total mastectomy rate was 19.5%; re-excision rate was 22.1% for women who had BCS. Approximately half had low DCIS Scores, and RT recommendations based on the DCIS Score were acceptable to most women. Clinical trial information: E4112.
Long-term outcome of breast cancer patients diagnosed ≤40 years according to breast cancer subtype in the absence of adjuvant systemic therapy: The PARADIGM initiative.
Authors: Dackus Gwen , ter Hoeve Natalie D , Opdam Mark , Vreuls Willem , Koop Esther A , Willems Stefan M. , Varga Zsuzsanna , Cordoba Alicia , Mooyaart Antien L , Groen Emilie , Broeks Annegien , Stathonikos Nikolas , Józwiak Katarzyna , Hauptmann Michael , Sonke Gabe S. , Van Der Wall Elsken , Siesling Sabine , van Diest Paul J. , Linn Sabine C. ,   PARADIGM Study Group
Published: September 2018

535

Background: Young age at breast cancer diagnosis is considered a poor prognostic factor. As a result, many treatment guidelines advice adjuvant systemic treatment for young patients. Answering prognostic questions on young patients has therefore become a challenge. The PARADIGM (PAtients with bReast cAncer DIaGnosed preMenopausally) project aims to assess the long-term outcome of women diagnosed with breast cancer ≤40 years in the absence of adjuvant systemic therapy, using real world data from the nationwide Netherlands Cancer Registry (NCR) coupled with tissue biobanking. Methods: All women ≤40 years, diagnosed in the Netherlands between 1989-2000 with a primary invasive, histologically proven, TanyN0M0 breast cancer, without adjuvant systemic treatment were identified through the NCR. Back then N0 patients were considered low risk and did not receive adjuvant systemic treatment. Tissue specimens were revised by a team of dedicated breast pathologists. Cox regression was performed to estimate hazard ratios for recurrence-free (RFS) and overall survival (OS) according to immunohistochemical (IHC) subtype. Analyses were adjusted for grade, pathological T-stage, histological subtype and radiotherapy. Results: We included 2310 patients with a mean follow-up of 15.4 years (range 0-25 years). OS for the whole cohort was 68% and RFS 58.4% at 25 years. In total 740 deaths and 1043 recurrences were observed. Hormone receptor (HR)+/HER2+ patients had a significantly worse OS when compared to HR-HER2+ patients (adjusted Hazard Ratio 1.58; 95% confidence interval 1.05-2.38; p=0.029). No difference was observed between HR-HER2+ and the triple negative and HR+/HER2- subgroups at 25-years. RFS was similar for all IHC subtypes. Conclusions: In this large cohort of non-adjuvant systemically treated young breast cancer patients with long-term follow-up HR+/HER2+ patients have a significantly worse survival when compared to triple negative, HR-/HER2+ and HR+/HER2- patients. The latter three subtypes have similar OS at 25 years. Future molecular studies have been planned to distinguish the favorable from the unfavorable prognostic patients.
Longer follow-up on cardiac safety and distant disease free survival of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab in patients with early-stage HER2-positive breast cancer.
Authors: Wang Rui , Yu Anthony Francis , Steingart Richard , Patil Sujata , Baselga Jose , Norton Larry , Hudis Cliff , Dang Chau T.
Published: September 2018

540

Background: We previously reported the cardiac safety results and distant disease-free survival (DDFS) on a phase 2 trial of dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H) in patients with early stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The incidence of congestive heart failure (CHF) was 1.4% both at a median follow-up of 2 and 7 years. Here, we report updated CHF and DDFS rates with longer follow-up. Methods: Patients were enrolled with HER2 overexpressed (immunohistochemistry 3+) or amplified (fluorescent in situ hybridization ratio > 2.0) disease, regardless of size or nodal status, and baseline left ventricular ejection fraction (LVEF) of > 55%. Patients (pts) received dd AC (60/600 mg/m2) q 2 weeks (w) x 4 →T (175 mg/m2) q 2 w x 4 with H (loading dose 4 mg/kg → 2 mg/kg q w during T → 6 mg/kg q 3 w for rest of 1 year); pegfilgrastim was administered after each chemotherapy cycle. LVEF monitoring with multigated acquisition scan occurred at baseline, months 2 (after AC), 6, 9, and 18 (after therapy completion). Results: From January 2005 to November 2005, 70 pts were enrolled; 2 (3%) and 68 (97%) were treated in neoadjuvant and adjuvant settings, respectively. In 68 pts treated in adjuvant setting, 40 (60%) and 27 (40%) had node-positive and node-negative disease, respectively. The median age was 49 years old (range 27-72); 55 (79%) had hormone-receptor positive disease, 11 (16%) had hypertension, and 21 (30%) had left sided radiation. The median baseline LVEF was 68% [range, 55%-81%]). With a median follow-up of 10.9 yrs, there was no additional CHF event. Therefore, the cumulative incidence of CHF remains to be 1.4% (95% confidence interval [95% CI], 1.36%- 7.7%). The 9 and 10 year DDFS rates were 89% (95% CI, 78%-94%) and 87% (95% CI 75%-93%), respectively. Conclusions: Longer follow-up of this study has demonstrated that ddAC →TH is associated with a low risk of CHF and promising DDFS in patients with early-stage HER2-positive breast cancer.
An estimation model for Oncotype Dx score using routine clinical and pathological parameters.
Authors: Ruiz Mendoza Rossana Esther , Namuche Fernando , Flores Claudio J. , Aguilar Alfredo , Gomez Henry Leonidas
Published: September 2018

548

Background: Oncotype Dx(ODX) prognosticates the risk of recurrence and predicts the benefit of adjuvant chemotherapy in estrogen-receptor-positive breast cancer (BC). However, its cost makes it prohibitive for many health care systems. Our objective is to develop a model using routine clinical and pathological parameters to estimate ODX high risk category to guide adjuvant chemotherapy decisions. Methods: We retrospectively reviewed ODX and pathology reports from 190 early BC patients (2014 to 2016) in a specialized cancer center. Variables were selected through a multiple linear regression model. Coefficients of statistically significant variables were used to build an equation. Its results were divided into 2 estimated risk categories. ODX RS was also divided into 2 categories; above or below 25 (cut-off in TAILORx and RxPONDER). The final locked model was independently validated in 57 patients. Results: Among the tested variables, tumor size (pT), progesterone receptor (PR), Ki67 and Elston-Ellis grade were significantly associated with ODX RS (Table 1). The linear predictor is: (0.2544 x pT) – (0.0739 x PR) + (0.0861 x Ki67) + (5.4232 x Elston grade). The threshold score for this equation was set on 13 (median value) to discriminate low and high estimated risks. The correct classification rate (CCR) for the training and validation sets was 60% and 56%, respectively. CCR for high risk was 72% and 87% in the training and validation sets, respectively. Conclusions: An equation based on readily available variables correctly classified more than half of cases. Although the overall CCR is modest, our equation is remarkably useful for high risk cases requiring chemotherapy. With further validation, our model could provide a clinically useful estimation of high risk at lower cost. [Table: see text]
Final results of the international randomized PORTEC-3 trial of adjuvant chemotherapy and radiation therapy (RT) versus RT alone for women with high-risk endometrial cancer.
Authors: de Boer Stephanie M. , Powell Melanie E. , Mileshkin Linda R. , Katsaros Dionyssios , Bessette Paul , Haie-Meder Christine , Ottevanger Petronella B , Ledermann Jonathan A. , Khaw Pearly , Colombo Alessandro , Fyles Anthony W. , Baron Marie-Helene , Kitchener Henry C. , Nijman Hans , Kruitwagen Roy F.P.M. , Jurgenliemk-Schulz Ina M. , Nout Remi A. , Smit Vincent T.H.B.M. , Putter Hein , Creutzberg Carien L. ,   PORTEC Study Group
Published: September 2018

5502

Background: Women with high-risk endometrial cancer (HREC) are at increased risk of distant metastasis and endometrial cancer-related death. The randomized PORTEC-3 intergroup trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (CTRT) versus pelvic radiotherapy (RT) alone for women with HREC. Methods: Women with HREC (FIGO stage I grade 3 with deep myometrial invasion and/or LVSI; stage II or III; or serous/clear cell histology) were randomly allocated (1:1) to RT (48.6 Gy in 1.8 Gy fractions) or CTRT (two cycles of cisplatin 50 mg/m² in week 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² at 3-week intervals) with stratification for participating center, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival (OS) and failure-free survival (FFS). The Kaplan-Meier method, log-rank test and Cox regression analysis were used for final analysis according to intention-to-treat. PORTEC-3 is registered with ISRCTN (ISRCTN14387080) and ClinicalTrials.gov (NCT00411138). Results: 686 women were enrolled between 2006 and 2013. 26 women were excluded; 13 withdrew consent early and 13 were ineligible, which left 660 patients in the analysis, with a median follow up time of 60.2 months (IQR 47.1–72.9): 330 CTRT and 330 RT. Three- and five-year OS for CTRT vs. RT was 84.4% versus 83.9%, and 81.8% versus 76.7%; overall HR 0.79 [95% CI 0.57-1.12, p=0.183]. Three-year FFS was 79.7% (CTRT) versus 71.8% (RT), and at 5 years 75.5% versus 68.9%, overall HR for FFS 0.77 [0.58-1.03, p=0.078]. Patients with stage III EC had lower 5-year FFS and OS compared to stage I-II (FFS 63.9% vs 78.9%, p<0.001, and OS 74.3% vs 83.1%, p=0.003). They also had greatest benefit of CTRT: 5-year FFS for stage III was 69.3% for CTRT vs 58.0% for RT [95% CI 0.45-0.97, p=0.032], and 5-year OS for stage III was 78.7 % vs 69.8% (p=0.114). Conclusions: Adjuvant chemotherapy given during and after pelvic radiotherapy for treatment of HREC did not significantly improve 5-year FFS and OS, compared with RT alone. For women with stage III EC FFS was however significantly improved with CTRT by 11% at 5 years. Follow-up will continue to evaluate long-term outcomes. Clinical trial information: NCT00411138.