bluuebunny/crossref_metadata_2025 huggingface dataset:
Results from a phase Ib/II study of enzalutamide and metformin in men with castration resistant prostate cancer (CRPC).
Authors: Parikh Mamta , Robles Daniel , Pan Chong-xian , Lara Primo , Yang Joy C , Gao Allen , Evans Christopher P.
Published: May 2019

5054

Background: Preclinical models have shown that autophagy is a cell survival mechanism to overcome treatment-induced stress and facilitate progression and resistance in CRPC. Metformin (met) demonstrates autophagy inhibition and resensitizes CRPC tumors to enzalutamide (enza) as a combination in in vitro models. A Phase Ib/II trial was conducted to evaluate the combination. Methods: Eligible patients (pts) had established CRPC, ECOG 0-2, adequate hematologic and organ function, and ≤ 2 prior treatments for CRPC. Major exclusion criteria included prior enza or met treatment, presence of brain metastases, history of DM2 or seizures. An initial cohort of 3 pts were treated with enza 160 mg PO daily and met 500 mg PO bid (DL1), with met dose escalated to 1000 mg PO bid (DL2) in subsequent 3 pts if dose-limiting toxicity (DLT) was observed in ≤1 pt in DL 1, and cycles of 28 days. Once primary objective of maximum tolerated dose (MTD) was established, additional pts were enrolled at MTD for a total of 24 evaluable pts. Secondary objectives of the study included PSA response and safety. Results: From 8/24/16-12/31/18, a total of 3 pts were enrolled to DL1, with no DLTs observed in that cohort, with an additional 21 enrolled to DL2; 12 remain on trial. Median age was 71, with 8/24 (33%) and 3/24 (12.5%) with prior docetaxel and abiraterone treatment, respectively. One DLT due to Grade 3 abdominal pain was observed at DL2 prior to establishing MTD. Grade 3 AEs observed in 1/24 (4%) of pts were diarrhea, fatigue, hypertension, lower GI bleed, myalgia; 2/24 (8%) had abdominal pain. One pt had Grade 4 hallucinations. Among pts who discontinued, 8 were discontinued for progression, 3 withdrew consent, and 1 experienced an SAE (seizure). Pts received median of 11 cycles (1-31) of treatment. PSA response ≥ 50% was observed in 19/24 (79%) pts. Conclusions: The combination of enzalutamide 160 mg PO daily and metformin 1000 mg PO bid is well-tolerated, and clinically active. Clinical trial information: NCT02339168.
A circulating tumor cell specific RNA assay for assessment of androgen receptor signaling inhibitor sensitivity in metastatic castration-resistant prostate cancer.
Authors: Teng Pai-Chi , Jan Yu Jen , Yoon Junhee , Chen Pin-Jung , Chen Jie-Fu , Yao Nu , Cheng Shirley , Lozano Amber , Freeman Michael , You Sungyong , Tseng Hsian-Rong , Posadas Edwin M.
Published: May 2019

5059

Background: Our objective is to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitors (ARSIs) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We developed NanoVelcro CTC-RNA Assay by combining Thermoresponsive(TR)-NanoVelcro CTC purification system with NanoString nCounter platform for CTC purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we selected the most aggressive and ARSI-resistant subtype- the PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop a CTC-PCS1 panel that is specific to PC CTCs. We validated NanoVelcro CTC-RNA Assay and CTC-PCS1 panel with PC cell lines to demonstrate sensitivity and specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PC patients receiving ARSIs to test in our assay. The PCS1 Z score of each sample was computed and compared with ARSI treatment sensitivity. Results: We established a 16-gene CTC-PCS1 panel that consists of CTC-specific RNA signatures. The validation studies using PC cell lines showed that the assay can detect the RNA transcripts with high sensitivity and scalability in the range of 1-100 cells. We also showed that the genes in CTC-PCS1 panel is highly expressed in PC cells. We further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016). Conclusions: Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance- a goal in precision oncology.
Computerized histomorphometric features of glandular architecture predict risk of biochemical recurrence following radical prostatectomy: A multisite study.
Authors: Leo Patrick , Janowczyk Andrew , Elliott Robin , Janaki Nafiseh , Shiradkar Rakesh , Farrè Xavier , Yamoah Kosj , Rebbeck Timothy , Shih Natalie , Khani Francesca , Robinson Brian D. , Eklund Lauri , Ettala Otto , Taimen Pekka , Bostrom Peter , Feldman Michael D , Gupta Sanjay , Lal Priti , Madabhushi Anant
Published: May 2019

5060

Background: Following a radical prostatectomy (RP) for prostate cancer, a patient may experience biochemical recurrence (BCR), defined as two consecutive prostate specific antigen (PSA) readings > 0.2 ng/mL. BCR is correlated with metastasis and disease specific survival. Extant molecular based companion diagnostic tests for predicting risk of BCR and disease progression tend to be expensive and tissue destructive. We sought to evaluate whether computer extracted features of glandular architecture from routine digitized H&E slides could predict post-RP BCR risk. Methods: RP specimens from 683 patients (184 with BCR, 499 without) with post-surgical PSA follow-up information were gathered from six sites. Median non-BCR follow-up was 3.2 years. A representative tumor area was annotated on the diagnostic H&E slide of each patient. 324 (131 BCR) patients from two sites formed the training set. The other 359 (53 BCR) patients formed the validation set. Glands were segmented by a deep learning model. 216 features describing gland arrangement, shape, and disorder were then extracted. An elastic net Cox proportional hazards model was constructed from the training set using the top 10 stable features identified via feature selection. Risk score thresholds were chosen on the training set to stratify patients into low-, medium-, or high-risk. Validation set results were evaluated by the log-rank test and hazard ratio. For the 172 (37 BCR) patients for whom Gleason grade and preoperative PSA values were available, risk classifications were compared using Cox proportional hazards regression. Results: Nine of the top features were gland shape features and one was a gland arrangement feature. The hazard ratio between the low- and high-risk groups on the validation set was 3.04 (p < 0.05). The histomorphometric classifier was predictive of BCR (p < 0.05, hazard ratio = 1.63) independent of Gleason grade group and preoperative PSA in multivariate testing. Conclusions: Computer extracted features of gland morphology can stratify post-RP patients by BCR risk. Our computerized histomorphometric model could serve as a prognostic tool in the post-RP setting.[Table: see text]
Evolving natural history of metastatic prostate cancer.
Authors: Nafissi Nellie , Bryce Alan Haruo , Kosiorek Heidi E. , Butterfield Richard , Ho Thai Huu , Singh Parminder , Tan Winston , Costello Brian Addis
Published: May 2019

5063

Background: The systemic therapies available to patients with metastatic prostate cancer (mPC) have improved dramatically over the past decade. Prior to 2010, the only agents with a proven survival benefit for patients with metastatic disease were androgen deprivation therapy and docetaxel. Since then, five new agents have been FDA approved and have proven survival benefit in phase III trials. Anecdotal experience suggests that the increased available lines of therapy have changed the profile of mPC to include a higher prevalence of visceral metastases. Methods: A retrospective review of 474 patients with prostate cancer who died in 2009 and in 2016 was performed. Patients with metastatic disease who had imaging within 6 months of death were included. A total of 164 patients were eligible for analysis. Results: Mean age at death overall was 77.4 years (SD 9.5) and did not differ signifiantly by cohort. Overall rates of visceral and distant metastases to include lung, liver, adrenal, brain, renal, spleen, and thyroid, were higher in patients who died in 2016 as compared to those who died in 2009 (40.0% and 26.1%, respectively, p = 0.07). Lung metastases were more prevalent in patients who died in 2016 versus in 2009 at 26.3% and 13.0%, respectively (p = 0.05). Patients who died in 2009 received a median of 3 (range 1-10) systemic treatments versus 4 (range 0-13) in those who died in 2016 (p = 0.005). Forty-four percent of patients who died in 2016 used five or more lines of systemic treatments compared to 26.1% of patients in 2009. Conclusions: The emergence of new systemic therapies for mPC is changing the natural history of the disease. Forty percent of patients now develop visceral metastases compared to 26% in the past. These changes will drive the need for new treatment approaches targeting visceral metastases. [Table: see text]
Ductal (PDC), acinar (PAC) and neuroendocrine (PNC) carcinomas of the prostate: A comparative comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Jacob Joseph , Shapiro Oleg , Liu Nick , Ferry Elizabeth Kate , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Ali Siraj Mahamed , Chung Jon , Schrock Alexa Betzig , Reddy Prasanth , Millis Sherri Z. , Alexander Brian , Necchi Andrea , Ross Jeffrey S.
Published: May 2019

5064

Background: PDC, PAC and PNC are histologic subtypes of prostate cancer (PC). We queried whether these subsets would share similar genomic alterations (GA) reflecting their disease biology and clinical features. Methods: CGP was performed using a hybrid capture-based assay on 61 PDC, 4,132 PAC and 217 PNC. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, GA per tumor and TP53 GA of PDC, PAC and PNC were similar (Table). RB1 GA were predominant in PNC. TMPRSS2:ERG fusions were most frequent in PNC, intermediate in PAC and lowest in PDC. AR GA were more often identified in PAC than PDC or PNC whereas PTEN GA were most frequent in PDC than PAC or PNC. Targetable GA were identified in all 3 groups when focused on BRCA2 (PARP inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC or PNC. BRAF GA (BRAF/MEK inhibitors) were more frequent in PDC and PAC than PNC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDC and PAC and low in PNC. Low frequencies of MSI-High and low median TMB levels were similar in all 3 groups. Conclusions: The pathologic features of PDC, PAC and PNC have been classically maintained as representative of 3 different tumor types with potentially contrasting histogenesis. In the current CGP based study, all 3 tumor types did not display significant differences in genomic signatures other than the high RB1 GA. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) especially in PDC and PAC. [Table: see text]
Randomized phase II trial of presurgical androgen deprivation therapy (ADT) with or without axitinib in prostate cancer (PCa) presenting with lymph node (LN) metastasis.
Authors: Zurita Amado J. , Slack Tidwell Rebecca , Troncoso Patricia , Chapin Brian Francis , Harris Deborah , Pisters Louis L. , Araujo John C. , Pettaway Curtis Alvin , Aparicio Ana , Tu Shi-Ming , Papadopoulos John N. , Wang Jennifer , Logothetis Christopher , Pagliaro Lance C. , Davis John W.
Published: May 2019

5078

Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]
Contemporary trends in treatment for low-risk prostate cancer.
Authors: Frankel Jason , Caumont Fernando , Pervin Ari , Porter Christopher R. , Flores John Paul
Published: May 2019

5082

Background: Active surveillance (AS) is the preferred management of low risk (LR) prostate cancer (PCa) to decrease morbidity associated with overtreatment. We hypothesized management trends would show AS increasing and initial definitive treatment decreasing for men with LR PCa. This study describes contemporary trends in initial treatment for LR PCa using the National Cancer Database (NCDB), which includes ~50% of new PCa diagnoses in the United States per year. Methods: NCDB was queried for all patients with LR localized PCa (2010-2015), defined as non-metastatic PCa with PSA<10 ng/mL, Gleason ≤6 and clinical T1-T2a primary tumor. Staging was assigned using 2018 American Joint Committee on Cancer guidelines. Patients refusing treatment, unable to be treated due to comorbidity or with unknown treatment status were excluded. Men were grouped based on NCDB codes for initial treatment including prostatectomy (PR), radiation (RT), AS and no treatment. Those receiving initial definitive treatment were compared to those who were not using logistic regression. Multivariable analysis was conducted for factors possibly correlating with management choice. Results: Of the 645,932 patients identified, 134,540 met inclusion criteria. Of these patients, 114,183 (84.9%) underwent PR or RT compared to 20,357 (15.1%) that did not. When examined over time, 92.4% of patients underwent initial PR or RT in 2010 vs. 73.9% in 2015 (p<0.001). 90% of patients seen at community cancer centers underwent definitive initial treatment compared to 78% of those seen at academic centers (p<0.001). Conclusions: In this national, hospital-based cohort overall rates of definitive initial treatment for LR PCa remain high, though seem to be decreasing over time. Overtreatment of LR PCa remains a concern and illustrates the relatively slow incorporation of guideline recommendations into clinical practice at the national level. [Table: see text]
Human prostate cancer immune phenotypes after androgen deprivation therapy.
Authors: Dallos Matthew , Obradovic Aleksandar , Chowdhury Nivi , Lopez Bujanda Zoila , Aggen David Henry , Hawley Jessica , Rathkopf Dana E. , Drake Charles G.
Published: May 2019

5083

Background: The prostate tumor microenvironment (TME) is generally non-inflamed. However, we previously showed in pre-clinical models that androgen deprivation therapy (ADT) induces a complex immune cell infiltrate. Whether ADT similarly promotes inflammation in patients remains unclear. Therefore, we collected specimens from patients with localized prostate cancer treated with neoadjuvant degarelix and hypothesized that we could decipher key changes in the immune TME after ADT utilizing a novel cancer systems biology approach. Methods: We identified a cohort of patients treated with neoadjuvant degarelix (240mg SQ) as part of two clinical trials (NCT01696877, NCT01542021). Patients were treated with degarelix either 4 days (N = 13), 7 days (N = 17) or 14 days (N = 8) prior to radical prostatectomy. RNA was extracted from FFPE tissue and analyzed by RNAseq. To deconvolute fractional contributions of different immune cell subsets we performed CIBERSORT and Uniform Manifold Approximation and Projection (UMAP) analysis. Treatment groups were compared to a cohort of untreated matched controls (N = 37). Results: Degarelix induced a complex immune cell infiltrate in human primary prostate tumors with an increase in both pro- and anti-inflammatory cells subsets and changes in expression of immune checkpoints compared to untreated matched controls. Degarelix therapy also significant changed associated gene signatures within the lymphoid and myeloid compartments over time. Conclusions: ADT leads to profound immune remodeling within the prostate TME. Our analysis of human primary prostate tumors supports the hypothesis that the optimal time for immunologic intervention is the peri-castration period. These data also suggest that combinatorial immunotherapy strategies that target particular immune cell subsets will likely be required to successfully promote robust anti-tumor immune responses in prostate cancer.
Immunophenotype and proliferation to predict for response to neoadjuvant chemotherapy in TNBC: Results from BrighTNess phase III study.
Authors: Metzger Filho Otto , Stover Daniel G. , Asad Sarah , Ansell Peter J , Watson Mark , Loibl Sibylle , Geyer Charles E. , O'Shaughnessy Joyce , Untch Michael , Rugo Hope S. , Huober Jens Bodo , Golshan Mehra , Sikov William M. , Von Minckwitz Gunter , Rastogi Priya , Maag David , Wolmark Norman , Denkert Carsten , Symmans William Fraser
Published: May 2019

510

Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and achievement of pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) remains unknown. Methods: RNA seq was performed on pre-tx research biopsies of stage II/III TNBC enrolled in BrighTNess. NAC regimens included paclitaxel alone or with carboplatin (Cb) or Cb plus veliparib, followed by AC. Computational analysis included subtyping (i.e. PAM50, Pietenpol), prolif (PAM50) and GeparSixto immune signature (GSIS). Cb-containing arms were combined due to similar pCR. Results: High quality RNA seq data was obtained from 482 of 634 pts. PAM50 classified 80.1% of tumors as basal-like. TNBC subtypes were mostly BL1 or BL2 (23.3%), IM (22.4%) or M/MSL (31.7%); 6% were LAR. pCR was higher for basal vs non-basal tumors (52.3% vs 35.4%, p = 0.003). IM had the highest pCR rate (64.2%, 95% CI 59.9%,68.5%). Basal-like was not a significant predictor for Cb benefit (p-interaction = 0.8). Prolif (OR = 0.30 p < 0.001) and GSIS (OR 0.68 p < 0.001) were significantly correlated with pCR but did not correlate with each other (Pearson’s r2 = 0.027). In multivariate analysis, prolif (HR = 0.36 95% CI, 0.21-0.61 p = 0.0002) and GSIS (HR = 0.62 95% CI, 0.49-0.79 p < 0.0001) increased the ability to predict pCR beyond standard clinico-pathologic variables (likelihood ratio = 14.9, p = 0.0001115). Among all pts, those above the median for both prolif. and GSIS had the highest pCR (67%; 84/125) while those below the median for both had the lowest pCR rate (34%; 42/125). Tumors with higher inferred CD8+ T-cell infiltration demonstrated greater benefit from Cb using either TIMER (HR = 0.83 [0.73-0.95]) or CIBERSORT (HR = 0.83 [0.76-0.91]). Tumors with higher inferred total macrophages, particularly immune suppressive M2 macrophages had a higher pCR rate on the non-Cb arm (AC-T) using CIBERSORT (HR = 1.27 [1.07,1.50]). Conclusions: Immunophenotype and proliferation are independent predictors of pCR to standard NAC regimens in TNBC. PAM50 is not a significant predictor of Cb benefit. Exploratory findings suggest that tumor infiltrating immunophenotype (i.e. CD8 T cells and macrophages) may predict response to specific NAC regimens in TNBC. Clinical trial information: NCT02032277.
Clinical validity of CTS5 for estimating risk of late recurrence in unselected, non-trial patients with early ER+ breast cancer.
Authors: Richman Juliet , Ring Alistair E. , Dowsett Mitchell , Sestak Ivana
Published: May 2019

514

Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological data to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with estrogen receptor positive (ER+) breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Methods: The validity of CTS5 was tested in a retrospective cohort of unselected, non-trial patients diagnosed with early ER+ breast cancer at the Royal Marsden Hospital from 2000-2007 who were alive and distant recurrence-free at 5 years. The primary endpoint was time to late DR (5-10 years). Cox regression models were used to determine the prognostic value of CTS5 and to produce Kaplan-Meier curves with associated 10-year DR risks (%). Results: A total of 2428 women were included with a median follow-up of 9.34 years from diagnosis. The CTS5 was significantly prognostic for late DR in post- and premenopausal women (Table). Risk stratification by CTS5 of the postmenopausal cohort was comparable with the development cohort. 42.1% of postmenopausal women were categorised into the low risk group with a late DR risk of 4.9% and these women had significantly lower risk of late DR compared to those in the intermediate or high-risk groups (Table). Amongst the premenopausal cohort, 41% were categorised as low risk with a late DR risk of 4.9%. The prognostic effect of CTS5 was seen for chemotherapy treated (HR=2.26, 95% CI (1.68-3.03)) and untreated patients (HR=1.93, 95% (1.32-2.82)). Conclusions: CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected, non-trial patients that included premenopausal women. The low risk cohort identified by the CTS5 represents a group of women whose risk of late DR is so low as to not warrant extended endocrine therapy to ten years. [Table: see text]
Event-free survival analysis of the prospectively randomized phase III ETNA study with neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) followed by anthracycline regimens in women with HER2-negative high-risk breast cancer.
Authors: Gianni Luca , Mansutti Mauro , Anton Antonio , Calvo Martínez Lourdes , Bisagni Giancarlo , Bermejo Begoña , Semiglazov Vladimir , Thill Marc , Chacon Jose Ignacio , Chan Arlene , Morales Serafin , Alvarez Isabel , Lahuerta Ainhara , Zambetti Milvia , Redfern Andrew D. , Dent Rebecca Alexandra , Barlera Simona , Valagussa Pinuccia , Tusquets Ignasi
Published: May 2019

515

Background: The ETNA study showed that substituting P with nab-P did not significantly increase the overall rate of pathological complete response (pCR) (P 18.6%, nab-P 22.5%, p = 0.19). The multivariate analysis revealed that tumor subtype (triple negative vs luminal B-like) was the most significant factor (OR 4.85) influencing treatment outcome (Gianni L et al, JAMA Oncol 2018). Methods: This multicenter open label study (NCT01822314) in collaboration with GEICAM and BCRC-WA randomized 695 patients with centrally-confirmed HER2-negative breast cancer to nab-P 125 mg/m2 (346 patients) or P 90 mg/m2 (349 patients). The two drugs were given on weeks 1, 2 and 3 followed by 1-week rest for 4 cycles before 4 cycles of an anthracycline regimen as per investigator choice. The primary endpoint was pCR (absence of invasive cells in breast and nodes). A secondary endpoint is event-free survival (EFS) defined as the time from randomization to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast cancer) after surgery or death due to any cause. Results: The ITT analysis of the secondary endpoint EFS at 5 years is reported below: Clinical trial information: NCT01822314. Overall 5-year survival was 84.8% after P and 87.3% for nab-P. No serious adverse events were documented during the follow-up. Conclusions: The improved 5-year EFS after nab-P failed to reach statistical significance (unadjusted P = 0.245). In the analysis by subgroup the numerical improvement was almost exclusively observed in luminal B and not in TN tumors. So far the data do not support substitution of P with nab-P in the schedule and doses adopted in the ETNA trial. Additional analyses will be based on ongoing molecular studies.[Table: see text]
Association between tumor biology and occult lymph node metastases before and after primary neoadjuvant therapy (NAT) for patients with early breast cancer.
Authors: Kolberg Hans-Christian , Kolberg-Liedtke Cornelia , Krajewska Maja , Bauerfeind Ingo , Fehm Tanja N. , Fleige Barbara , Helms Gisela , Lebeau Annette , Staebler Annette , Loibl Sibylle , Untch Michael , Kuehn Thorsten
Published: May 2019

518

Background: Scientific efforts aim at a reduction of axillary morbidity through reduced axillary intervention among patients with early breast cancer. However, it is still unclear if this approach is feasible in all subtypes based on their risk of axillary involvement. We analyzed the association of tumor biology and occult axillary involvement with data from arms A and B of the SENTINA trial (Kühn T et al., Lancet Oncol 2013). Methods: Patients were included if they presented with a clinically negative axilla before NAT (arms A and B) and stratified according to tumor biology. All patients received SLNB before NAT, in cases of negative SLNB without further axillary surgery (Arm A) and in cases of positive SLNB (Arm B) with SLNB and axillary dissection after NAT. Logistic and linear regression analyses were carried out to evaluate the association between tumor biology and axillary involvement before and after NAT. Results: Of the 1022 patients in arms A and B of the SENTINA trial 926 were evaluable for this analysis. Of these, 27.9% had triple negative (TN), 16.3% hormone receptor (HR) and HER2 positive (triple positive = TP), 47.6% HR positive and HER2 negative (luminal) and 8.2% HR negative and HER2 positive (HER2) tumors. 39.7% of the luminal, 28.9% of the HER2, 19% of the TN and 47% of the TP tumors had involved SLN before NAT. Subgroup comparisons showed a significant difference between luminal and TN (p < 0.0001), whereas the differences between luminal and TP (p = 0.115) and HER2 (p = 0.077) were not statistically significant. The 317 patients with involved SLN prior to NAT received SLNB and axillary dissection after completion of NAT. The analysis after NAT showed trends for lower rates of involved lymph nodes for the high-risk groups (TN 20% / TP 14.3% / HER2 8.7%) compared to luminal tumors (27.6%) without reaching statistical significance. Conclusions: Our analysis demonstrates that among patients enrolled in the SENTINA trial, patients with triple negative disease have the lowest risk for occult lymph node metastases at initial presentation. Our results do not justify more intense local intervention among patients with triple negative breast cancer.
Adherence to adjuvant endocrine therapy after breast cancer in Sweden 2008-2010: A nationwide survey.
Authors: Andersson Anne , Von Wachenfeldt Väppling Anna , De Jong Anna , Nyström Lennarth
Published: May 2019

523

Background: In estrogen receptor (ER) positive early breast cancer (EBC) adjuvant endocrine therapy (AET) is crucial to reduce recurrence and mortality. Previous studies have shown that adherence to AET is lower than expected and could negatively affect outcome. Since the year of 2000, BC patients in Sweden are treated in accordance to national guidelines. Treatment is offered at a low cost for the patient. The aim of the study was to estimate the adherence to AET in Sweden by regions and age groups. Methods: Women with a first primary EBC diagnosis 2008-2010 were identified through the Swedish Cancer Registry (SCR). Individual tumour and treatment data were retrieved from the Swedish National Breast Cancer Registry (SNBCR). Patients with ER negative tumours, small tumours (≤ 10 mm) and metastatic disease was excluded from the study since there were no indication to AET. Likewise, were individuals with AET registered to be administered by a third part excluded. Dispensed treatment from pharmacies was obtained through the Swedish Prescription Registry and medication possession rate (MPR) was calculated as number of dispensed doses divided by treatment duration in days. Good adherence to treatment in a patient was set at MPR ≥ 80 %. Adherence was calculated for 3 and 5 years. Results: Twenty-one thousand sixteen (21 016) individuals with a first primary BC between 2008 and 2010 was identified through SCR of which 20 596 were registered in the SNBCR. A total of 10 176 met the inclusion criteria in the study. Adherence after 3 years was 88.0 % and after 5 years 82.5 %. Adherence differed between regions in Sweden and was positively associated with age at diagnosis between 41-74 years. Urban areas had a lower adherence than rural areas (80.7 % vs 83.6 %; p= <0.001). Conclusions: Adherence to AET in Sweden was good, although there were differences by age and urban and rural areas. Further studies are needed to identify factors affecting differences in adherence, with the purpose of initiate actions to increase adherence to AET in ER positive EBC patients.
De-escalating adjuvant trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer: A systemic review and meta-analysis.
Authors: Goldvaser Hadar , Yasmin Korzets Ceder , Shepshelovich Daniel , Yerushalmi Rinat , Sarfaty Michal , Ribnikar Domen , Thavendiranathan Paaladinesh , Amir Eitan
Published: May 2019

524

Background: One year of adjuvant trastuzumab in combination with chemotherapy is the standard of care in early-stage HER2 positive breast cancer. Existing data on shortening trastuzumab treatment show conflicting results. Methods: A search of PubMed and conferences identified randomized trials that compared abbreviated trastuzumab therapy to one year of treatment in early-stage HER2 positive breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for disease free survival (DFS) and overall survival (OS). Data on the number of DFS and distant relapse events were also collected as were the number of patients at risk in each group. Subgroup analyses evaluated the effect of nodal involvement, estrogen receptor (ER) expression and the duration of abbreviated trastuzumab (9-12 weeks versus 6 months). Odds ratios (ORs) and 95% CI were computed for pre-specified cardiotoxicity events including cardiac dysfunction and congestive heart failure (CHF). Results: Analysis included 6 trials comprising 11603 patients. In most studies adjuvant chemotherapy included anthracyclines and taxanes. Shorter trastuzumab treatment was associated with worse DFS (HR = 1.14, 95% CI 1.05-1.25, p = 0.002) and OS (HR = 1.15, 95% CI 1.02-1.29. p = 0.02). The effect on DFS was not influenced by ER status (p for the subgroup difference = 0.23), nodal involvement (p = 0.44) or the different duration of trastuzumab in the experimental arm (p = 0.08). In absolute terms, after an estimated median follow-up of 71 months, shorter treatment with trastuzumab was associated with an absolute increase in DFS events of 2.3%. Shorter trastuzumab treatment was associated with lower odds of cardiac dysfunction (OR = 0.67, 95% CI 0.55-0.81, p < 0.001) and CHF (OR = 0.66, 95% CI 0.50-0.86, p = 0.003). Conclusions: Compared to one year, shorter duration of adjuvant trastuzumab is associated with significantly worse DFS and OS, despite favorable cardiotoxicity profile. One year of trastuzumab should remain the standard adjuvant treatment in early-stage HER2 positive breast cancer with appropriate cardiac monitoring.
A randomized phase III trial comparing dose-dense epirubicin and cyclophosphamide (ECdd) followed by paclitaxel (T) with paclitaxel plus carboplatin (PCdd) as adjuvant chemotherapy for early triple-negative breast cancer patients with high-recurrence risk.
Authors: Wang Jiani , Li Qing , Mu Yuxin , Zhang Tongtong , Han Ying , Wang Jiayu , Li Qiao , Luo Yang , Yuan Peng , Ma Fei , Fan Ying , Zhang Pin , Xu Binghe
Published: May 2019

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Background: There are no well-established adjuvant chemotherapy (AC) regimens for early triple negative breast cancer (TNBC). Our randomized phase III trial was designed to compare dose dense paclitaxel plus carboplatin (PCdd) with commonly used dose dense epirubicin and cyclophosphamide, followed by paclitaxel (ECdd-T) regimen as AC for TNBC with high recurrence risk. Methods: Between May 2011 and November 2015, TNBC patients were randomized in 1:1 ratio to receive PCdd or ECdd-T regimen as AC every two weeks for 8 cycles with administration of granulocyte stimulating factor (G-CSF) support. The primary endpoint was 3-year disease free survival (DFS).The secondary endpoints included overall survival (OS) and safety. Survival analyses were also performed for different subgroups stratified by age status (≤40 years vs >40 years), Ki 67(<50 vs ≥50), tumor size (<2cm vs ≥2cm), nodal status (N- vs N+) and treatment free survival (TFS) (<30 days vs ≥30 days). Results: In total, 132 patients with a median age of 49 years (PCdd 64 patients, ECdd-T 68 patients) were enrolled. After a median follow-up of 57.3 months, 23 events were observed (18 in ECdd-T, 5 in PCdd). Patients in the PCdd arm had significantly higher DFS rate than that in the ECdd-T arm (log-rank p = 0.0046, hazard ratio (HR) 0.305, 95% confidence interval (CI) = 0.134-0.693). The 3-year DFS rate was 93.7% with PCdd versus 77.9% with ECdd-T,respectively. Difference in 3-year OS rate was observed between the two arms (98.4% vs 92.6%), significantly higher in the PCdd arm ( p = 0.0268). Both regimens were well tolerated with manageable adverse events(AEs). Worse neutropenia (Grade 3/4: 48.5% in ECdd-T vs. 21.9% in PCdd, p=0.002) was found in ECdd-T arm. 3-year DFS rate for PCdd was superior in the following subgroups, age>40 years, clinically evaluated lymph nodes, TFS <30 days, with statistical significance ( p <0.05). Conclusions: Our data suggested that PCdd was superior to ECdd-T as AC for early TNBC in terms of improving 3-year DFS and OS. PCdd with lower hematological toxicity might be an appropriate regimen for early TNBC patients with high recurrence risk. Clinical trial information: NCT01378533.
EPHA genetics for prediction of paclitaxel-induced peripheral neuropathy sensitivity.
Authors: Marcath Lauren A , Kidwell Kelley M. , Smith Ellen M. Lavoie , Vangipuram Kiran , Gersch Christina L , Burness Monika Leigh , Griggs Jennifer J. , Van Poznak Catherine H. , Hayes Daniel F. , Henry Norah Lynn , Beutler Andreas S. , Hertz Daniel Louis
Published: May 2019

532

Background: Chemotherapy induced peripheral neuropathy (CIPN) is a common, debilitating paclitaxel side effect that has been primarily attributed to cumulative systemic paclitaxel exposure. Paclitaxel dose-adjustment to achieve target systemic exposure decreases but does not eliminate severe CIPN, suggesting some patients are inherently CIPN-sensitive. Ephrin ( EPHA) polymorphisms have been reported to increase CIPN occurrence (Baldwin 2012, Leandro-Garcia 2013, Boora 2016) but replication has been challenging, perhaps due to the inability to isolate CIPN-sensitivity by accounting for systemic exposure differences. The study purpose was to determine if EPHA genetic variants previously associated with CIPN occurrence are associated with CIPN-sensitivity. Methods: PN was assessed at baseline and weekly using the 8-item sensory subscale (CIPN8) of the patient-reported EORTC CIPN20 in patients receiving paclitaxel 80 mg/m2 weekly x 12. EPHA4, EPHA5, EPHA6, and EPHA8 were sequenced in germline DNA. Associations with higher PN-sensitivity were tested for three genetic models (total variants, coding variants, and rs7349683) by incorporating genetics into previously published CIPN8 predictive models that included measured paclitaxel exposure. Significant associations were tested for association with higher risk of PN-related treatment disruption (i.e. dose decrease, delay, or discontinuation). Results: In the 59 included patients, carrying EPHA5 rs7349683 was associated with greater CIPN sensitivity (beta coefficient: 0.40, standard error: 0.14, p = 0.005), indicating these patients had a greater increase in CIPN8 during treatment than would be predicted based on cumulative paclitaxel exposure. Rs7349683 was not associated with increased PN-induced treatment disruption, perhaps due to the low number of events (n = 19). Conclusions: Using a novel approach that isolates CIPN-sensitivity by accounting for measured paclitaxel exposure, our results provide further evidence that EPHA5 rs7349683 may be a promising marker for CIPN. If additional validation studies confirm this association, genetic testing could enable personalized treatment strategies to prevent CIPN in patients with breast cancer.
Additional prognostic value of OncoMasTR multigene prognostic signature to clinicopathological information in patients with HR-positive, HER2-negative, lymph node-negative breast cancer from the TAILORx Tissue Bank, Ireland.
Authors: O'Connor Darran , Kelly Catherine Margaret , Crown John , Russell Niamh , Barron Stephen , Loughman Tony , Lynch Seodhna , O'Grady Anthony , Sheehan Katherine M , Fay Joanna , Saha Anurati , Dynoodt Peter , Fender Bozena , Wang Chan-Ju Angel , O'Leary Desmond , Bracken Adrian P. , Rahman Arman , Gonzalez Claudia Aura , Attar Nebras Al , Gallagher William M.
Published: May 2019

535

Background: Multigene prognostic signatures (MGPS) can identify early stage breast cancer patients who may require less aggressive treatment. To be clinically useful, MGPSs must provide additional prognostic information to clinicopathological information routinely used by clinicians. The OncoMasTR MGPS was discovered via a novel bioinformatic transcriptional network analysis. OncoMasTR consists of genes – Master Transcription Regulators (MTRs) – that regulate previously known prognostic genes and have identified functional roles in several hallmarks of cancer including proliferation, invasion and metastasis. The OncoMasTR Molecular Score (OM) consists of just 3 MTRs. The OncoMasTR Risk Score (OncoMasTR) combines OM with lymph node status and tumour size, and categorises patients as low or high risk. The OncoMasTR Test has been analytically and clinically validated. Methods: MTR expression was measured by RT-qPCR in tissue from 404 patients enrolled in an independent translational trial (NCT02050750) that collected tissue and clinical data from patients enrolled in TAILORx in Ireland. OM, OncoMasTR and Oncotype DX Recurrence Score (RS) were compared on the additional prognostic value they provided to Ki67, Nottingham Prognostic Index (NPI) and other clinicopathological information for distant recurrence (DR) and invasive disease (ID). Results: OM (LRχ2 = 20.3, p < 0.00001, c-index = 0.84) and OncoMasTR (LRχ2 = 22.6, p < 0.00001, c-index = 0.85) were significantly prognostic, and more prognostic than RS (LRχ2 = 8.4, p = 0.004, c-index = 0.73) for DR. OM and OncoMasTR provided more additional prognostic information than RS to Ki67, NPI, tumour size, tumour grade, and age for DR. Similar results were found when OM, OncoMasTR and RS were compared on prognostic performance for ID. Conclusions: OM and OncoMasTR were significantly prognostic for DR and ID and added significant prognostic value to Ki67, NPI, and other clinicopathological information. Furthermore, OM and OncoMasTR showed superior prognostic performance to RS.
Factors associated with twenty-year (y) risks of breast cancer-specific mortality (BCSM) in the Surveillance, Epidemiology, and End Results (SEER) Registry.
Authors: Leone Jose Pablo , Vallejo Carlos Teodoro , Hassett Michael J. , Leone Julieta , Freedman Rachel A. , Tolaney Sara M. , Leone Bernardo Amadeo , Lin Nancy U. , Winer Eric P.
Published: May 2019

540

Background: Most reports describing the risk of late relapse in breast cancer have been based on selected patients (pts) enrolled into clinical trials. The aims of this study were to report on population-based long-term risks of BCSM, and the risks of BCSM conditional on having survived 5 y. Additionally, we aimed to identify factors associated with late deaths from breast cancer. Methods: Using SEER data, we identified women with breast cancer (T1-T2, N0-N2, M0) between 1990-2005, with one primary cancer in their lifetime, and known hormone receptor (HR) status. We used Kaplan-Meier analyses to determine the effect of baseline variables on cumulative risks of BCSM, we estimated annual rate of events per 100 person-years, and performed Cox regression stratified by HR status. Results: We included 202,080 pts (median follow-up = 12.25 y). Of all breast cancer deaths, the proportion after 5 y was 65% for HR+ vs 28% for HR- (p < 0.001). The table shows risks of BCSM by HR and N status, and annual event rates. The cumulative risk of BCSM in y 5-20 ranged from 7.9% in HR-N0 to 38% in HR+N2. Among HR+ pts, adjusted risks of BCSM conditional on having survived 5 y were higher for T2 vs T1a (Hazard ratio [HzR] 3.3, p < 0.001), N2 vs N0 (HzR 3.5, p < 0.001), age at diagnosis (dx) > 64 y vs < 50 y (HzR 1.4, p < 0.001), black race vs white (HzR 1.3, p < 0.001) and grade III vs I (HzR 2.3, p < 0.001). For HR- pts, adjusted risks of BCSM conditional on having survived 5 y were higher for T2 vs T1a (HzR 2.0, p < 0.001), N2 vs N0 (HzR 2.8, p < 0.001) and age at dx > 64 y vs < 50 y (HzR 1.6, p < 0.001). Conclusions: For HR+ breast cancer, risks of BCSM remain high beyond 5 y from dx and depend on T-N status, age, race and grade. In HR- breast cancer, the risk of BCSM is highest within 5 y from dx; however, risks beyond 5 y are still considerable and depend on T-N status and age. Our results underscore the need for better adjuvant therapies in both HR+ and HR- breast cancer. [Table: see text]
A novel 95-gene signature (Curebest 95GC Breast) that predicts recurrence-risk in patients with ER-positive, HER2-negative, node-negative, early-stage primary invasive breast cancer with an intermediate Oncotype DX Recurrence Score.
Authors: Fujii Takeo , Masuda Hiroko , Cheng Yee Chung , Yang Fei , Sahin Aysegul A. , Naoi Yasuto , Matsunaga Yuki , Raghavendra Akshara Singareeka , Sinha Arup Kumar , Espinosa Fernandez Jose R. , James Anjali , Yamagishi Keisuke , Matsushima Tomoko , Tripathy Debu , Tada Sachiyo , Jackson Rubie S. , Noguchi Shinzaburo , Nakamura Seigo , Acoba Jared David , Ueno Naoto T.
Published: May 2019

542

Background: The TAILORx trial demonstrated that adjuvant endocrine and chemoendocrine therapies had similar efficacy in patients with hormone receptor-positive, HER2-negative, node-negative breast cancer with an Oncotype DX recurrence score (RS) of 11-25. However, a predictive strategy is needed to identify patients with intermediate RS who may benefit from adjuvant chemoendocrine therapy. Curebest 95GC Breast (95GC) is a 95-gene signature that can stratify patients into two groups with high (95GC-H) and low (95GC-L) groups to predict the risk of recurrence. Our primary objective was to show that 95GC can classify patients with intermediate RS into binary recurrence risk groups. Methods: Patients with ER-positive, HER2-negative, node-negative invasive breast cancer and RS 11-30 who underwent definitive surgery and adjuvant endocrine therapy were included. RNA was derived from archived formalin-fixed, paraffin-embedded samples, and 95GC was calculated as reported previously. The Fisher exact and Brunner-Munzel tests were used to compare variables between 95GC groups. A Kaplan-Meier estimate with a log-rank test was used for recurrence-free survival (RFS) analysis. Results: The analysis included 178 patients from five institutions. The 5-year RFS rate in patients with RS 18-30 was higher in the 95GC-L group (n = 129, 96.3%) than in the 95GC-H group (n = 49, 90.9%; p = 0.002), which was consistent with results in an independent Japanese population (n = 224; p < 0.001). RFS rates significantly differed between the groups among patients with RS 11-25 as well (95GC-L, 97.4%; 95GC-H, 87.1%; p = 0.001). RFS rates did not differ between patients with RS 18-25 (94.8%) and those with RS 26-30 (93.8%; p = 0.33). Conclusions: 95GC can predict recurrence risk in patients with ER-positive, HER2-negative, node-negative invasive breast cancer and intermediate RS. Further prospective retrospective studies in the TAILORx population are warranted to confirm that 95GC can identify patients who may benefit from adjuvant chemoendocrine therapy.