bluuebunny/crossref_metadata_2025 huggingface dataset:
Androgen deprivation therapy in the treatment of prostate cancer and dementia risk: A systematic review and meta-analysis.
Authors: Nead Kevin Thomas , Sinha Sumi , Nguyen Paul L.
Published: September 2018

5044

Background: Androgen deprivation therapy (ADT) to treat prostate cancer may be associated with an increased risk of dementia, but existing studies have shown conflicting results. Here we conduct a systematic review and meta-analysis on the association of ADT in the treatment of prostate cancer with the risk of dementia. Methods: We conducted a systematic review of articles reporting the outcome of dementia among individuals with prostate cancer in those exposed to ADT versus a lesser-exposed comparison group (e.g. no ADT, intermittent ADT) using the PRISMA statement guidelines. Two authors independently carried out searches in PubMed (1966–present), Web of Science (1945–present), Embase (1966–present), and PsycINFO (1806–present). The search was undertaken December 4th, 2016. We assessed the validity of each study per the Newcastle-Ottawa Scale criteria. We meta-analyzed studies reporting an effect estimate and controlling for confounding.Random- or fixed-effects meta-analytic models were used in the presence or absence of heterogeneity, respectively, per the I2statistic. Small study effects were evaluated using Egger and Begg’s tests. Results: Nine studies were included in the systematic review. Seven studies reported an adjusted effect estimate for dementia risk. A random-effects meta-analysis of studies reporting any dementia outcome, which included 50,541 individuals, showed an increased risk of dementia among ADT users (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.08–2.00; p = 0.02). We separately meta-analyzed studies reporting all-cause dementia (HR, 1.46; 95% CI, 1.05–2.02; p < 0.001) and Alzheimer’s disease (HR, 1.25; 95% CI, 0.99–1.57; p = 0.06). The I2statistic to evaluate the proportion of heterogeneity due to study variation was 76% (95% CI, 47–89; p < 0.001) for the primary analysis. There was no evidence of bias from small study effects (Egger, p = 0.19; Begg, p = 1.00). Conclusions: The currently available combined evidence suggests that ADT in the treatment of prostate cancer may be associated with an increased risk of dementia. The potential for neurocognitive deficits secondary to ADT should be discussed with patients and evaluated prospectively.
Genome-wide analysis of metastases to reveal association of pathway activation with abiraterone acetate/prednisone (AA/P) primary resistance and cell cycle proliferation pathway activation with response duration in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Wang Liewei , Dehm Scott , Hillman David W. , Sicotte Hugues , Gormley Michael , Bhargava Vipul , Li Weimin , Tan Winston , Pitot Henry C. , Ho Thai Huu , Costello Brian Addis , Bryce Alan H. , Zhenqing Ye , Vedell Peter T , Barman Poulami , Jimenez Rafael E. , Carlson Rachel , Wang Liguo
Published: September 2018

5053

Background: Genomic aberrations associated with resistance/response to AA/P are not known. In a prospective study we assessed whole-exome/RNA-seq based aberrations in CRPC metastatic biopsies for identifying molecular markers associated with primary resistance and response duration. Methods: Sequencing of metastatic biopsies was performed for analyzing molecular aberrations that predict primary resistance (defined as progression at 12-weeks of therapy (non-responders) using PSA, RECIST, bone scan criteria per PCWG2). Gene network analysis was performed in genes mutated more frequently in non-responders and in genes differentially expressed between non-responders and responders using a “risk ratio” (RR) of ≥2. Cox regression models with multiple gene network pathways were used for determining association with time to treatment change (TTTC). Results: Of 92 enrolled pts 82 had complete whole-exome, RNA-seq & 12-week outcome data available for analysis. At 12-weeks 33/82 had progressed. Using a RR of ≥2, 113 genes were more frequently mutated in non-responders & 292 in responders. In non-responders, gene network analysis revealed frequent mutations in Wnt/β-catenin pathway genes; frequent deletion of negative regulators of Wnt pathway ( DKK4, SFRP2, LRP6). Gene expression analyses revealed significantly reduced expression levels of Wnt/β-catenin pathway inhibitors and increased expression levels of cell cycle proliferation (CCP) genes in non-responders. Median study follow up was 32 months during which time 58/82 pts progressed and switched treatments. Median TTTC was 10.1 months (IQR:4.4-24.1). In multivariate analysis CCP scores of ≥50 predicted shorter TTTC (HR = 2.11, 95% CI: 1.17-3.80; p = 0.01). Conclusions: In metastases Wnt/β-catenin pathway activation is associated with primary AA/P resistance and increased CCP with acquired drug resistance. These findings offer molecular based predictive biomarkers in CRPC stage treatment. Clinical trial information: NCT#01953640.
Effect of Ga-68 PSMA-11 PET on management in patients with recurrent prostate cancer.
Authors: Hope Tom , Aggarwal Rahul Raj , Greene Kirsten L , Chee Bryant , Tao Dora , Feng Felix Yi-Chung , Chang Albert , Cooperberg Matthew R. , Ryan Charles J. , Small Eric Jay , Carroll Peter
Published: September 2018

5057

Background: PET imaging of prostate specific membrane antigen (PSMA) has been shown to have a higher sensitivity and specificity compared to conventional imaging. The objective was to evaluate the impact of PSMA PET on the management of prostate cancer patients with biochemical recurrence following local therapy. Methods: In our initial Ga-68-PSMA-11 PET protocol (NCT02611882), 150 patients with biochemical recurrence were imaged. 63 patients were imaged using PET/CT (GE Discovery VCT) and 63 patients using PET/MRI (GE Signa 3.0T PET/MRI). 110 patients received Lasix injections. Referring clinicians filled out a pretreatment management form and a management form based on the imaging results. Changes in management were graded as major, minor, no change or unknown based upon the responses. Results: We received both pre and post imaging forms in 126 patients, for an 84% response rate. The average PSA in the population was 5.9 ± 5.4 ng/mL with an average doubling time of 9.7 ± 11.0 months, and 60 patients had a PSA of less than 2.0 at the time of imaging. The average time between prior treatment and imaging (RP and/or radiation) was 5.3 ± 5.4 years, with 46 patients imaged within two years of their most recent treatment. 43 patients had a prior prostatectomy, 41 prior radiation, and 33 patients had both. 103 patients (82%) had disease localized on PSMA imaging. Of the 126 patients, 67 (53%) of the imaging studies resulted in a major change in management. The most common major change was converting from active surveillance to radiation therapy (15 patients, 12%), changing from ADT to radiation therapy (16 patients, 13%), and converting from radiation therapy to either active surveillance (6 patients, 5%) or to ADT alone (3 patients, 2%). 10 patients (8%) had a minor change, 42 patients (33%) had no change, and 7 patients (6%) had an unknown change in management. Conclusions: The results of our surveys demonstrate a substantial impact of PSMA PET on the intended patient management. The majority of changes involved converting a targeted therapy to systemic treatment or systemic treatment to a targeted therapy. Prospective studies are warranted to determine whether directed treatment towards PSMA-avid lesions affects long-term disease outcomes. Clinical trial information: NCT02611882.
Comprehensive molecular profiling of multi-focal prostate cancer and concomitant lymph node metastasis: Implications for tissue-based prognostic biomarkers.
Authors: Salami Simpa Samuel , Hovelson Daniel H , Mathieu Romain , Kaplan Jeremy B , Susani Martin , Rioux-Leclercq Nathalie , Shariat Shahrokh F. , Tomlins Scott A. , Palapattu Ganesh S.
Published: September 2018

5061

Background: Current tissue-based prognostic biomarker assays claim that assessment of a single biopsy focus is sufficient to predict disease behavior. We analyzed and compared the genetic profiles of multifocal prostate cancer (PCa) with concordant lymph node metastasis (LNM) to determine if expression-based prognostic tests are robust to multifocality. Methods: This IRB-approved study comprised patients who underwent radical prostatectomy and lymph node dissection that revealed N1 or discordant multifocal (low- and high-grade foci) disease. DNA and RNA were co-isolated from each tumor focus pre-identified on formalin fixed paraffin embedded specimens. High depth, targeted DNA and RNA next generation sequencing was performed to characterize the molecular profile of each sample, using the Oncomine Comprehensive (11 patients) or Comprehensive Cancer (DNA, 3 patients) Panels and a custom targeted RNAseq panel comprising genes for deriving prognostic signatures. Results: A total of 67 primary tumor and 17 LNM foci from 14 patients were analyzed. We observed significant intra- and inter-patient molecular heterogeneity. For example, in patient #1, while all 4 regions of high-grade primary tumor showed TP53 somatic mutations and some copy number alterations (CNAs) with two samples from the LNM, tumor areas near the positive margin showed more complete concordance than intraprostatic regions. Critically, a low-grade primary tumor focus in this case showed no somatic mutation or CNA overlap with the high-grade or LNM samples. In patient #4, all tumor and LNM foci shared a large number of somatic mutations, including a frameshift mutation in PTEN, with no high level CNA, consistent with a hypermutated genotype. By targeted RNAseq, low- and high-grade tumors from the same patient showed distinct expression profiles using genes included in prognostic signatures. Conclusions: Our results challenge the claim that expression-based prognostic tests are robust to multifocality. Further studies are needed to better characterize the biologically dominant lesion in multifocal PCa and hold promise for the development of improved prognostic biomarkers.
Association of loss of tumor suppressor ZFP36 with lethal prostate cancer.
Authors: Sweeney Christopher , Gerke Travis , Beltran Himisha , Sboner Andrea , Karnes R. Jeffrey , Klein Eric A. , Davicioni Elai , Yousefi Kasra , Ross Ashley , Mucci Lorelei , Trock Bruce J.
Published: September 2018

5062

Background: Inflammation has been linked to prostate cancer (PCa) progression which may be mediated by the transcription factor nuclear factor kappa B (NFκB). Using a bioinformatic screen focused on NFκB pathway activation in lethal PCa, we identified the tumor suppressor ZFP36 as a key node of the NFκB network. We also showed in vitro that ZFP36 expression was inversely associated with both NFκB-controlled gene levels and proliferation and sensitivity to enzalutamide. We examined the role of ZFP36 and PCa progression in patient cohorts. Methods: The association between low mRNA expression of ZFP36 (levels in the lower quartile) and lethal PCa (defined as metastatic disease or death) was assessed with logistic regression among men with localized PCa in two independent cohorts treated with radical prostatectomy (RP). The discovery cohort was RP samples from Health Professional Follow-up Study and Physicians Health Study and the validation cohort was RP samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and MSKCC. In a third cohort from Cornell University, ZFP36 expression levels were assessed in RP samples from patients with localized PCa and biopsies of metastatic castration resistant prostate cancer (mCRPC). Results: Table 1 shows men with localized PCa and lower quartile of tumor ZFP36 expression had a nearly 2-fold higher risk of lethal PCa after adjusting for known clinical and histological prognostic features (age, RP Gleason score, T-stage); an association confirmed in the validation cohort. ZFP36 gene expression was also significantly lower in mCRPC (n=53) compared with a localized RP cohort (n=68) (p-value <0.0001). Conclusions: In humans lower ZFP36 in RP specimens is associated with clinically significant risk of lethal PCa after treatment with curative intent and lower ZFP36levels are found in metastatic tissue. [Table: see text]
Serum androgens and survival in metastatic castration resistant prostate cancer (mCRPC) patients treated with docetaxel and prednisone: Results from CALGB 90401 (Alliance).
Authors: Ryan Charles J. , Dutta Sandipan , Kelly William Kevin , Middleberg Rob , Russell Carly , Small Eric Jay , Morris Michael J. , Taplin Mary-Ellen , Halabi Susan
Published: September 2018

5067

Background: Higher baseline androgens have been previously shown to be associated with an improved overall survival (OS) in mCRPC patients treated with the androgen synthesis inhibitors, ketoconazole or abiraterone. The purpose of this analysis was to determine whether baseline serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA (D) are associated with OS in mCRPC patients treated with docetaxel-based chemotherapy. Methods: Data from 1,050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were used. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment serum assays for T, A and D were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS) at NMS labs. The proportional hazards model was used to assess the prognostic significance of T, A, and D in predicting OS adjusting for known prognostic factors. Results: Median values for T, A, and, D were 1.00, 13.00 and 8.12, ng/dL respectively.Values above the median were defined as low, above as high. Median OS for low vs high levels was 22.7 and 23.1 month for T, 22.4 and 21.7 month for A and 21.8 and 24.0 month for D, respectively, all NS. In multivariable analysis adjusting for 10 known prognostic values and prior keto use in mCRPC (Halabi JCO 2014), A (p-value = 0.013) levels were associated with OS. The HR for A was = 0.99 (95% CI = 0.98-0.99). Conclusions: In multivariate analysis, baseline androstenedione levels are prognostic factors for OS in mCRPC patients receiving chemotherapy. Low or undetectable levels of other androgens are associated with shorter OS, consistent with prior results in androgen synthesis inhibitor treated pts in both the chemotherapy naive and post chemotherapy settings. This relationship may reflect more aggressive tumor biology that evolves in an extreme androgen deprived milieu. Clinical trial information: NCT00110214.
Translating prostate cancer working group (PCWG) criteria into a quantitative progression biomarker in metastatic castration resistant prostate cancer (mCRPC).
Authors: Anand Aseem , Heller Glenn , Scher Howard I. , Morris Michael J.
Published: September 2018

5068

Background: mCRPC is a bone dominant lethal disease. A validated endpoint in mCRPC trials is bone scan progression, which is semi-quantitative and rely on the appearance of new lesions as proposed by the PCWG. The validated automated bone scan index (BSI) quantifies the bone tumor burden as the fraction of total skeletal weight. To build on the current definition of disease progression, we sought to compare the association of time to progression with overall survival (OS) using PCWG criteria and BSI increase. Methods: mCRPC patients (pts) enrolled on trials of agents targeting androgen-receptor (AR) were assessed. Pts were required to have a raw bone scan image for BSI analysis concurrent with disease assessments. The EXINI automated computing platform generated the BSI values. Thresholds for the absolute and relative increase in BSI from 1st follow-up (≤12 weeks) were explored for the time to BSI progression. The association with survival time was computed for each threshold defined time to BSI progression. Kendall’s Tau, derived from the Clayton copula, was used to associate time to BSI progression with survival time, where both endpoints may be censored. Results: A total of 257 pts were assessed, of whom 169 had raw bone scans images needed for the BSI analysis. 90 pts (53%) met progression by PCWG criteria, the association between the time to PCWG progression and OS was 0.52. The association between time to BSI progression and OS was comparable to the PCWG progression when the absolute increase in BSI was 0.6 or more (table below). Conclusions: Progression in bone can be expressed as a single quantitative metric that describes the increase in total disease burden while retaining the same association that PCWG has with OS. These data represent the first steps to a quantitative expression of bone disease progression as a clinical trials endpoint. [Table: see text]
A phase III trial of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2+ breast cancer: The TRAIN-2 study (BOOG 2012-03).
Authors: Van Ramshorst Mette S. , van Werkhoven Erik , Mandjes Ingrid A. , Kemper Inge , Dezentjé Vincent O. , Oving Irma M. , Honkoop Aafke H. , Tick Lidwine W , Van de Wouw Agnes W , Mandigers Caroline M , Wesseling Jelle , Vrancken Peeters Marie-Jeanne , Linn Sabine C. , Sonke Gabe S. ,   Dutch Breast Cancer Research Group (BOOG)
Published: September 2018

507

Background: Neoadjuvant chemotherapy with dual HER2 blockade boosts pathologic complete response (pCR) rates in HER2+ breast cancer. The optimal chemotherapy backbone in this setting is unknown. We conducted a multicenter phase III trial to study whether anthracyclines would improve outcome compared to a carboplatin-taxane regimen (NCT01996267). Methods: We randomly assigned (1:1) patients with stage II-III HER2+ breast cancer to receive 9 cycles paclitaxel (80mg/m2 day 1 and 8) and carboplatin (AUC = 6mg/ml·min) (arm A) or 3 cycles 5-fluoruoracil (500mg/m2), epirubicin (90mg/m2), and cyclophosphamide (500mg/m2) followed by 6 cycles paclitaxel and carboplatin (arm B). Both arms received trastuzumab (6mg/kg, loading dose 8mg/kg) and pertuzumab (420mg, loading dose 840mg) concurrent with all chemotherapy cycles, and cycles were repeated every 3 weeks. The primary endpoint was pCR in breast and axilla (ypT0/is,ypN0). Results: 438 patients were included and 418 (arm A 206 vs arm B 212) were evaluable for the primary endpoint. The pCR rate did not differ between arms (arm A 68% [95% CI 61-74] vs arm B 67% [95% CI 60-73], p = 0.75). Hormone receptor (HR) negative tumors had significantly higher pCR rates (87% vs 54%, p < 0.0001), but we found no evidence for treatment-by-HR interaction (p = 0.23). Common adverse events grade ≥3 were neutropenia (arm A 53% vs arm B 57%, p = 0.34), febrile neutropenia (arm A 2% vs arm B 11%, p = 0.0001), and diarrhea (arm A 17% vs arm B 12%, p = 0.14). Neuropathy grade ≥2 was common in both arms (arm A 31% vs arm B 29%, p = 0.83), while left ventricular ejection fraction (LVEF) decline grade ≥2 (defined as ≥10% decline from baseline or LVEF < 50%) was more common in arm B (arm A 18% vs arm B 29%, p = 0.007). Symptomatic left ventricular systolic dysfunction was rare ( < 1%) in both arms. Conclusions: Anthracyclines increase the incidence of febrile neutropenia and grade ≥2 LVEF decline, but do not improve pCR rate in the contemporary neoadjuvant treatment of HER2+ breast cancer with dual HER2 blockade. Therefore, we currently favor a carboplatin-taxane based regimen. Follow-up is required to confirm these results with regard to long-term outcome. Clinical trial information: NCT01996267.
Identification of low prostate-specific antigen, high Gleason prostate cancer as a unique hormone-resistant entity with poor survival: A contemporary analysis of 640,000 patients.
Authors: Yang David Dewei , Mahal Brandon Arvin Virgil , Sweeney Christopher , Trinh Quoc-Dien , Feng Felix Yi-Chung , Nguyen Paul L.
Published: September 2018

5080

Background: The clinical implications of a low prostate-specific antigen (PSA) in high-grade prostate cancer are unclear. We examined the prognostic and predictive value of a low PSA in high-grade prostate cancer. Methods: We identified 642,975 patients in the National Cancer Database (n = 491,505) and Surveillance, Epidemiology, and End Results program (n = 151,470) with localized or locally advanced prostate cancer from 2004-2013. Patients were stratified by Gleason score (8-10 vs. ≤7) and PSA (≤2.5, 2.6-4.0, 4.1-10.0, 10.1-20.0, and > 20.0 ng/mL) for analyses. Multivariable Fine-Gray competing risks and Cox regressions were used to analyze prostate-cancer specific mortality (PCSM) and all-cause mortality (ACM), respectively. Results: 5.6% of Gleason 8-10 tumors were diagnosed with PSA ≤2.5 ng/mL. Among Gleason 8-10 disease using PSA 4.1-10.0 ng/mL as referent, PCSM was U-shaped with respect to PSA, with adjusted hazard ratio (AHR) of 1.75 (95% CI 1.05-2.92, P = 0.032) for PSA ≤2.5 ng/mL vs. 1.31, 0.88, and 1.60 for PSA 2.6-4.0, 10.1-20.0, and > 20.0 ng/mL. In contrast, PCSM was linear for Gleason ≤7 disease with AHR of 0.32 (95% CI 0.10-1.00, P = 0.050) for PSA ≤2.5 ng/mL vs. 1.13, 1.69, and 3.22 for PSA 2.6-4.0, 10.1-20.0, and > 20.0 ng/mL (PGleason*PSA interaction< 0.001). Gleason 8-10 disease with PSA ≤2.5 ng/mL had a much higher risk of PCSM than standard NCCN high-risk disease (AHR 1.92, 95% CI 1.18-3.14, P = 0.009; 47-month PCSM 14.0% vs. 10.5%). For Gleason 8-10 tumors treated with definitive radiotherapy, androgen deprivation therapy (ADT) was associated with decreased ACM for PSA > 2.5 ng/mL (AHR 0.87, 95% CI 0.81-0.94, P < 0.001) but trended toward increased ACM for PSA ≤2.5ng/mL (AHR 1.27, 95% CI 0.89-1.81, P = 0.194; PADT*PSA interaction= 0.026). Conclusions: Low PSA, high-grade prostate cancer appears to be a unique hormone-resistant entity with a high risk of PCSM that responds poorly to standard treatment. Further molecular classification and trials are urgently needed to develop biological insight into this entity and establish new treatment paradigms, potentially including chemotherapy or novel systemic agents.
Phase 3 randomized study of adjuvant anastrozole (A), exemestane (E), or letrozole (L) with or without tamoxifen (T) in postmenopausal women with hormone-responsive (HR) breast cancer: The FATA-GIM3 trial.
Authors: Perrone Francesco , Gallo Ciro , De Laurentiis Michele , Bisagni Giancarlo , Arpino Grazia , Sarobba Maria Giuseppa , Riccardi Ferdinando , Russo Antonio , Del Mastro Lucia , Cogoni Alessio Aligi , Cognetti Francesco , Gori Stefania , Frassoldati Antonio , Amoroso Domenico , Laudadio Lucio , Moscetti Luca , Montemurro Filippo , Nuzzo Francesco , Carlini Paolo , De Placido Sabino ,   On Behalf of GIM Investigators
Published: September 2018

515

Background: Uncertainty still exists regarding the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors (AI) and no trial has ever compared all the three AI. Methods: FATA-GIM3 is a multicenter, open label, 2x3 factorial phase 3 randomized study of adjuvant A, E and L upfront (UP - for 5 years) or sequentially (SEQ - for 3 years after 2 years of T) in postmenopausal HR breast cancer pts. Two comparisons were planned: UP vs SEQ and A vs E vs L. DFS (including local or distant relapse, second breast or non-breast cancer, DCIS and death, whichever came first) was the primary end-point; 2% at 5 yrs (corresponding to a HR of 0.79) was defined as the minimum difference required to declare superiority of UP vs SEQ. With two-tailed alfa 0.05, power 80%, 669 events and the enrolment of 3600 patients were planned. Following Data Monitoring Committee advice, final analysis was performed after 5yrs median follow-up. For each comparison a Cox regression model was applied adjusted by stratification factors and stratified by the other treatment factor. Analyses were based on intention-to-treat. Results: from 3/2007 to 7/2012, 3697 patients were enrolled at 76 centres. Median age 64, pT1 69.7% , pN0 64.3%, ER and PgR positive 88.9%, HER2 positive 8.9%, previous chemotherapy 38.3%. At 60 months median follow-up, 401 events were reported. 5yrs DFS was 89.8 with UP and 88.5 with SEQ (delta 1.32%, 95% CI -0.90-3.54; HR 0.89, 95% CI 0.73-1.08; P=0.23). 5yrs DFS was 90.0 with A, 88.0 with E and 89.4 with L (P=0.19). Conclusions: in the FATA-GIM3 trial there is a small non statistically significant DFS advantage for UP vs SEQ. No significant difference is evident among the three AI. Supported by the FARM5K3MEE AIFA grant from the Italian Drug Agency. Clinical trial information: NCT00541086.
Standard anthracycline-based vs. docetaxel-capecitabine in early breast cancer: Results from the chemotherapy randomization (R-C) of EORTC 10041/ BIG 3-04 MINDACT phase III trial.
Authors: Cardoso Fatima , Piccart-Gebhart Martine J. , Rutgers Emiel J. , Litière Saskia , Van't Veer Laura , Viale Giuseppe , Pierga Jean-Yves , van den Berkmortel Franchette W.P.J. , Brain Etienne , Gomez Patricia , Goulioti Theodora , Knox Susan , Luporsi Elisabeth , Nitz Ulrike , Rubio Isabel T , Stork Lisette , Vuylsteke Peter , TRYFONIDIS KONSTANTINOS , Bogaerts Jan , Delaloge Suzette
Published: September 2018

516

Background: The MINDACT trial demonstrated that 46% of breast cancer patients (pts) at high clinical (C) but low genomic (G) risk based on MammaPrint (70-gene signature), might safely forego adjuvant CT (Cardoso NEJM 2016). A second 1:1 randomization (R-C) was optional in all pts for whom CT was decided, between standard anthracycline-based regimens (AT) and experimental docetaxel 75 mg/m² IV + oral capecitabine 825 mg/m² bid x 14 days (DC), q3wks for 6 cycles after surgery. Methods: MINDACT included 6693 pts, of whom 2895 received CT. C-low/G-low pts were allocated to no CT, C-high/G-high to CT and those with discordant G/C results were randomized to use either G or C risk to decide use of CT. Primary endpoint for R-C was disease-free survival (DFS). Secondary endpoints included OS and safety. Statistical hypothesis: HR-0.76 in favour of DC. Results: A total of 1301 pts (45%), of whom 787 (61%) were C-high/G-high, 351 (27%) C-high/G-low, 137 (11%) C-low/G-high, and 26 (2%) C-low/G-low, were randomized to AT or DC. Main reason for not inclusion in R-C was CT given outside the trial. Compliance rates for R-C were 97% overall. At 5-years median follow-up, DFS was not significantly different between AT (649 pts) and DC (652 pts) [HR = 0.83 (0.60- 1.15, p = 0.263], and OS was similar in both arms (HR 0.91, 95% CI, 0.54- 1.53). For the relevant C-high/G-high group, DFS was also not different (5-years DFS 86.1 vs 88.1%; HR 0.83, 95% CI, 0.58-1.21). Of note, number of events is still small (AT: 30; DC: 27). Commonest adverse events in DC were grade 2 hand/foot syndrome (28.5% vs 3.3%), grade 2 diarrhea (13.7% vs 5.8%) and grade 1 peripheral neuropathy (27.1% vs 11.2%). Grade 2 anemia (14.2% vs 5.1%) and grade 4 neutropenia (24.6% vs 20.5%) were higher in AT. Cardiac events occurred in 9 pts overall, including 1 cardiac failure (AT), while 53 pts developed secondary cancers (AT: 32; DC: 21; leukemia: 2 in AT vs. 1 in DC). Four deaths occurred (AT:1 and DC:3) while on therapy. Conclusions: Docetaxel-capecitabine did not improve DFS or OS, compared with standard anthracycline-based CT, including for the C-high/G-high group. Safety profile of both regimens was as expected. Clinical trial information: NCT00433589.
Effects of neoadjuvant chemotherapy (NAC) on tumor infiltrating lymphocytes (TIL) and PD-L1 expression in the SWOG S0800 clinical trial.
Authors: Pelekanou Vasiliki , Barlow William E. , von Wahlde Marie-Kristin , Wasserman Brad , Lo Ying-Chun , Hayes Daniel F. , Hortobagyi Gabriel N. , Gralow Julie , Tripathy Debu , Livingston Robert B. , Porter Peggy , Nahleh Zeina A. , Rimm David L. , Pusztai Lajos
Published: September 2018

519

Background: Higher baseline TILs and PD-L1 expression are associated with greater pathologic complete response (pCR) rates, but how chemotherapy affects these immune parameters is unknown. The goal of this study was to examine TIL and PD-L1 expression in pre- and post-NAC tumor specimens from the S0800 clinical trial that compared weekly nab-paclitaxel/bevacizumab + dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel + AC as NAC for HER2-negative cases. Association between immune parameters, pCR and NAC-induced changes were tested using ER and NAC-arm adjusted logistic regression. Methods: TILs were assessed on H&E stained full sections of 120 pre- and 62 post-NAC tissues (tumor bed of pCR) including 59 matched samples. PD-L1 immunohistochemistry was performed using the FDA cleared 22C3 assay and results were available for 121 baseline and 43 matched post-NAC samples. Results: At baseline, the mean TIL count was 18%; 16% had no TILs and 9% had > 50% TILs. Higher baseline TILs were associated with higher pCR rate (p = 0.043, trend test p = 0.014) but there was no interaction with NAC arm. Post-NAC, the mean TIL counts was 11%; 5% had no TILs and 1.6% had > 50% TILs. In the matching post-NAC samples, the mean change was 15% decrease in TILs, but in 32% of cases TILs increased. Cases with residual disease (n=44) had lesser average decrease (p=0.029) than cases with pCR (n=15). The post-NAC decrease in TILs was also observed after excluding cases with pCR. At baseline, PD-L1 expression either in the stroma or on epithelial cells or in both was detected in 52 (43%) of 121 cases (5 tumor only, 29 stroma only, 18 tumor + stroma). Those with baseline PD-L1 expression had higher pCR (63% vs. 37%; p=0.008). Post-NAC, PD-L1 expression was seen in 14 of 43 (33%) cases (7 stroma only, 7 tumor + stroma). In the 39 matching pre- and post-NAC samples, PD-L1 expression was negative in both in 20, positive in both in 10 cases and 6 patients had PD-L1 expression at baseline but not in the post-NAC sample. Conclusions: TIL counts and PD-L1 expression generallydecreased, but in a minority of cases increased after NAC. The decrease in TIL was significantly greater in cases achieving pCR. Clinical trial information: NCT00856492.
Anastrozole after tamoxifen in early breast cancer patients with chemotherapy-induced ovarian function failure.
Authors: Tjan-Heijnen Vivianne C. , Van Hellemond Irene , Vriens Ingeborg , Peer Petronella , Swinkels Astrid , Smorenburg Carolien H. , Van Der Sangen Maurice , Kroep Judith R. , de Graaf Hiltje , Honkoop Aafke H. , Erdkamp Frans , van den Berkmortel Franchette , De Boer Maaike , de Roos Wilfred , Linn Sabine C. , Imholz Alexander , Seynaeve Caroline ,   Dutch Breast Cancer Research Group (BOOG)
Published: September 2018

523

Background: The DATA study compared 6 and 3 years of anastrozole therapy in postmenopausal women with hormone-receptor positive early breast cancer previously treated with 2-3 years tamoxifen (oral presentation SABCS 2016 #S01-03). The study included postmenopausal women, allowing those with chemotherapy-induced ovarian function failure (CIOFF). However, these may be at risk of ovarian function recovery (OFR). The current analysis compared the survival of women with CIOFF with definite postmenopausal women and examined the influence of OFR on survival. Methods: We selected patients from the DATA study aged 45-57 years at randomization who had received (neo-)adjuvant chemotherapy. They were classified by menopausal status at randomization (definite postmenopausal before chemotherapy or by ovariectomy, versus CIOFF). The latter were monitored by estradiol measurements for OFR during anastrozole. Endpoints: Disease-free Survival (DFS), Distant Recurrence-free Survival (DRFS), and Overall Survival (OS), corrected for tumor size, nodal status, grade, and hormone-receptor status. We used the landmark method to calculate residual 5-year survival rates. Results: In total, 261 patients were definite postmenopausal and 395 had CIOFF, of whom 39 experienced OFR while 290 did not (66 were excluded from the landmark analysis because follow-up estradiol levels were lacking). When comparing the CIOFF with the definite postmenopausal women, the 5-year survival rates were not significantly different. Within the group with CIOFF, experiencing OFR was associated with a trend for worse outcome (DFS-event HR 1.33 (95% CI 0.61-2.90), P=0.48; DRFS-event HR 2.11 (95% CI 0.89-5.02), P=0.09; and OS-event HR 2.24 (95% CI 0.92-5.45), P=0.07). Patients who experienced OFR in the first year had a residual 5-year rate for DFS of 73.1% compared with 87.4% in those who did not. For DRFS these rates were 76.9% vs. 92.1%, and for OS 80.8% vs. 94.4% respectively. Conclusions: These results suggest that women with CIOFF undergoing anastrozole treatment may be at increased risk of disease recurrence if experiencing OFR despite close monitoring of estradiol levels and adjusting endocrine treatment. Clinical trial information: NCT00301457.
Impact of DNA repair deficiency signature on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313).
Authors: Sharma Priyanka , Barlow William E. , Godwin Andrew K. , Knight Laura A , Walker Steven M. , Kennedy Richard D. , Badve Sunil S. , Gokmen-Polar Yesim , Pathak Harsh B , Isakova Kamilla , Linden Hannah M. , Tripathy Debu , Hortobagyi Gabriel N. , Hayes Daniel F.
Published: September 2018

529

Background: Biomarkers of response and resistance to adjuvant chemotherapy for TNBC are needed. Deficiency in DNA damage response (DDR) and repair pathways have been reported in TNBC and may impact response to chemotherapy. Aims: To investigate DNA damage response deficiency (DDRD) molecular signature, BRCA1mRNA expression and Tumor Infiltrating Lymphocytes (TILs) as prognostic markers in TNBC patients treated with adjuvant AC on S9313. Methods: S9313 accrued 3125 early stage BC patients to two alternative schedules of AC with no difference in outcomes between the two arms. We identified 425 (14%) patients with centrally determined TNBC with tissue availability. DDRD signature (44 gene signature, Almac Inc.) and BRCA1expression (NanoString nCounter) were performed on RNA isolated from pre-treatment FFPE tumor tissue. DDRD score was classified in quartiles. TILs evaluation was performed using previously described criteria. Markers were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for randomized treatment assignment. Results: For 425 TNBC patients median age: 45 yrs, and 5 year DFS and OS = 74% and 82%, respectively. DDRD signature was successfully evaluated in 89.6% (381/425) but only 267 (62.8%) met 60% tumor content criterion for inclusion. DDRD score quartiles were associated with DFS (5 year DFS 59% & 82% in the lowest & highest quartiles respectively, p = 0.0005) and OS (5 year OS 74% and 86% in lowest and highest quartiles respectively, p = 0.008). BRCA1 expression and TILs were successfully determined in 78% and 99% samples, respectively. BRCA1expression was not associated with DFS. TILs were associated with DFS (10% increase HR = 0.88; 95% CI 0.79-0.97; p = 0.016) and OS (HR = 0.84; 95% CI 0.74-0.94; p = 0.0005). DDRD score and TILs were highly correlated (Pearson = 0.62). In multivariate model of DFS including TILs and DDRD quartiles, only DDRD remains significant (p = 0.018). Conclusions: DDRD signature was prognostic in TNBC patients treated with AC chemotherapy and has the potential to be used as a selection criterion to identify TNBC patients whose prognosis is sufficiently poor to justify evaluation of alternative treatment.
Prognostic value of histopathology, stromal tumor infiltrating lymphocytes (sTILs) and adjuvant chemotherapy (AdjCT) in early stage triple negative breast cancer (TNBC).
Authors: Leon-Ferre Roberto Antonio , Polley Mei-Yin , Liu Heshan , Gilbert Judith A. , Cafourek Victoria , Hillman David W. , Elkhanany Ahmed , Akinhanmi Margaret , Negron Vivian , Boughey Judy Caroline , Liu Minetta C. , Ingle James N. , Kalari Krishna R. , Couch Fergus , Visscher Daniel W. , Goetz Matthew P.
Published: September 2018

533

Background: Current guidelines define TNBC as complete absence of estrogen (ER) and progesterone receptor (PR), without HER2 amplification. However, the prognostic impact of clinical and histopathological factors, sTILs, and AdjCT in TNBC meeting these strict criteria is unknown. Methods: From a cohort of 9985 women who underwent upfront surgery for M0 breast cancer (BC) at Mayo Clinic Rochester from 1985-2012, 1159 pts with ER negative or low (≤10%) BC were identified for central ER/PR/HER2 staining and HER2 FISH (IHC2+ only) to select those with TNBC by modern definitions. Cox proportional hazards models were used to assess the impact of clinicopathological variables on invasive disease-free (IDFS) and overall survival (OS). Results: Tumors from 605 pts (median age 56.3 yrs) met criteria for TNBC (ER < 1%, PR < 1% and HER2 0, 1 or 2+ and FISH negative). 51% were T1, 65% N0, 88% grade 3, and 75% had Ki67 > 15%. Histologically, 39% were anaplastic, 26% invasive ductal, 16% medullary, 8% metaplastic, 6% apocrine and 5% others. Median sTILs was 20% (0-90%). 55% pts received AdjCT [21% anthracycline (A), 19% A + taxane, and 15% other]. Median follow-up for IDFS and OS were 7.4 and 10.6 yrs, respectively. Multivariate analyses demonstrated that higher N stage (p < 0.01), lower sTILs (p = 0.01) and no AdjCT (p < 0.01) were independently associated with worse IDFS and OS. Histology (medullary subtype) was associated with better IDFS in univariate (HR 0.56, 95% CI, 0.35-0.89) but not in multivariate analyses, once sTILs were accounted for. Among systemically untreated pts (n = 182), higher N (p < 0.01) and lower sTILs (p = 0.04) were associated with worse IDFS. For systemically untreated T1N0 pts (n = 111), the 5-yr IDFS was 70% (95% CI, 61-81) [T1a: 83% (95% CI, 63-100), T1b: 68% (95% CI, 52-88) and T1c: 67% (95% CI, 55-83)], compared to 78% (95% CI, 68-84) for T1N0 pts treated with AdjCT. Conclusions: In TNBC pts, N stage, sTILs and receipt of AdjCT were independently prognostic for IDFS and OS. sTILs remained prognostic for IDFS in systemically untreated TNBC. In N0 TNBC, the risk of recurrence or death was substantial in the absence of chemotherapy, even for those with T1 tumors.
Adjustments in relative dose intensity (RDI) for FECD chemotherapy in breast cancer: A population analysis.
Authors: Veitch Zachary William Neil , Khan Omar Farooq , Tilley Derek , Xanthoula Kostaras , Tang Patricia A. , King Karen M. , Lupichuk Sasha M.
Published: September 2018

547

Background: Reductions in RDI of adjuvant chemotherapy for breast cancer (BC) has been associated with inferior survival. However, earlier studies may be confounded by uncharacterized BC subtype(s) (TNBC, HER2+) and non-taxane chemotherapy regimens (CMF, AC). This retrospective study evaluates survival (DFS/OS) outcomes for patients receiving RDI reductions for FECD adjuvant chemotherapy in Alberta, Canada. Methods: Patients with stage I-III, ER +/-, HER2- BC receiving adjuvant FECD chemotherapy from 2007-2014 were identified using the Alberta Cancer Registry. RDI of individual chemotherapeutics (cycle 1-6) were recorded. Average RDI was stratified by <85% vs ≥85% of total dose. Subgroup analysis for early (cycle 1-3) versus late (cycle 4-6) RDI reductions were evaluated. Events (recurrence/death) from any cause were identified. Results: FECD patients (n=1304) receiving an average RDI <85% (range 25-84%) compared to ≥85% demonstrated a significant decline in DFS (79% vs 85%; p<0.01) and OS (82% vs 89%; p<0.01). Early reductions (any) compared to no reduction in RDI were correlated with inferior DFS (77% vs 86%; p<0.01) and OS (79% vs 90%; p<0.01). Late reductions in RDI did not affect DFS/OS. Proportions of TNBC were non-significant for comparative cohorts. Significantly more N0 and N1-3 patients were seen in the any and no early reduction cohort respectively. Conclusions: In high risk BC patients, average RDI <85% is correlated with reduced DFS/OS for FECD. Early (FEC) compared with late (docetaxel) reductions in RDI are correlated with inferior survival. This data suggests that where possible, total (<85%) and early (FEC) dose reductions should be avoided in patients receiving adjuvant FEC-D chemotherapy. [Table: see text]
Toxicity of extended adjuvant aromatase inhibitors therapy in postmenopausal breast cancer patients: A systematic review and meta-analysis.
Authors: Goldvaser Hadar , Ribnikar Domen , Barnes Tristan Alexandra , Cescon David W. , Ocana Alberto , Amir Eitan
Published: September 2018

549

Background: Aromatase inhibitors (AI) are a gold standard adjuvant endocrine therapy for postmenopausal women with breast cancer. A number of randomized trials (RCTs) have reported modest improvements in breast cancer outcomes from extending treatment with AI beyond the initial 5 years after diagnosis. However, less in known about the toxicity of extended AI compared with no therapy. Methods: We conducted a systematic review of MEDLINE to identify RCTs that compared extended AI to placebo or no treatment. The search was supplemented by a review of abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CI), absolute risks, and the number needed to harm (NNH) associated with one adverse event were computed for prespecified safety and tolerability outcomes including cardiovascular disease, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation due to adverse events and death without recurrence. Results: Seven trials comprising 16349 patients met the inclusion criteria. Longer treatment with AI was associated with increased odds of cardiovascular disease (OR = 1.18, 95% CI 1.00-1.40, P=0.05; NNH = 122) and bone fractures (OR = 1.34, 95% CI 1.16 - 1.55, P < 0.001; NNH = 72). Compared to control, longer AI therapy was associated with a higher odds of treatment discontinuation due to adverse events (OR = 1.45, 95% CI 1.25 - 1.68, P < 0.001; NNH = 20). Longer AI therapy did not influence the odds of second cancers (OR = 0.93, 95% CI 0.73-1.18, P = 0.56). There was a numerical excess of death without recurrence with longer AI therapy, but this was not statistically significant (OR = 1.11, 95% CI 0.9 - 1.36, P = 0.34). Conclusions: Longer durations of AI use are associated with increased cardiovascular events and bone fracture. There is a numerical, but non-statistically significant excess of deaths without breast cancer recurrence among patients receiving longer AI therapy. These data should be taken into account when considering extended adjuvant AI therapy for breast cancer patients.
Disparities in multigene signature testing and its impact on adjuvant therapy in early stage breast cancer.
Authors: Jones Maris S. , Goldfarb Melanie , Wang Mansen , Ho Emily
Published: September 2018

550

Background: Commercially available prognostic multigene signature tests (PMT) have been available for over a decade to guide adjuvant therapy in early stage breast cancer. This study explores persistent disparities in the availability of PMT and how results influence the use of adjuvant therapy. Methods: Females > 18 years of age with newly diagnosed, primary, Stage I-III, ER positive, HER2-neu negative breast cancer that did not receive neoadjuvant therapy between 2006-2014 were captured from the National Cancer Database (NCDB) participant user file. Univariate and multivariate analyses identified factors associated with utilization of PMT as well as receipt of adjuvant chemotherapy for patients with PMT risk stratification. Results: Of 574,921 eligible females, 130,297 (22.66%) received PMT. Almost all patients that had PMT had pathologically negative (pN0 = 83%) or 1-3 positive LNs (pN1 = 16%). Controlling for tumor features, patients least likely to have PMT were of lower socioeconomic status, uninsured, not White non-Hispanic, < 40 or > 70 years of age, and treated at community hospitals or in the Western region (all p < 0.001). Very few patients with PMT results actually received adjuvant chemotherapy (0.64% of 92,235). Of this small group, younger patients (ages 18-49) those with less education (OR = 1.37, 95%CI:1.07-1.76), positive lymph nodes, and larger tumors (OR = 1.62, 95%CI:1.37-1.91) were more likely to receive adjuvant chemotherapy whereas patients with PR positive tumors (OR = 0.33, 95%CI:0.18-0.60) and those treated at academic facilities (OR = 0.81, 95%CI:0.68-0.96) were less likely to receive adjuvant chemotherapy after controlling for competing factors. Intermediate (OR = 5.34, 95%CI: 4.42-6.45) or high risk (OR = 32.65, 95%CI: 25.74-41.43) PMT scores had the greatest impact on receipt of adjuvant chemotherapy regardless of nodal status. Conclusions: Common socioeconomic and racial/ethnic disparities exist for PMT testing, though inappropriate use (high T or N stage) was minimal. Since PMT results strongly influenced recommendation of adjuvant therapy, decreasing disparities and making PMT available to all patients that are deciding on adjuvant therapy should be a priority.
An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers.
Authors: Hollebecque Antoine , Meyer Tim , Moore Kathleen N. , Machiels Jean-Pascal H. , De Greve Jacques , López-Picazo José María , Oaknin Ana , Kerger Joseph N. , Boni Valentina , Evans T.R. Jeffry , Kristeleit Rebecca Sophie , Rao Shangbang , Soumaoro Ibrahima , Cao Z. Alexander , Topalian Suzanne Louise
Published: September 2018

5504

Background: Treatment options for cervical, vaginal, and vulvar (GYN) cancers are limited after first-line therapy. Human papillomavirus (HPV) infection is associated with squamous cell carcinomas of the cervix (≥90%) and vulva/vagina (40–70%), and may elicit an immune reaction. Programmed death (PD)-1 and its major ligand PD-L1 are expressed in GYN cancers and inhibit immune responses. Nivolumab disrupts PD-1–mediated signaling, restoring antitumor immunity. Methods: In CheckMate 358 (NCT02488759), an ongoing multicohort study of 5 virus-associated cancers, PD-L1–unselected adults with R/M GYN cancers, ECOG PS 0–1, and ≤2 prior systemic therapies for R/M disease were eligible to receive nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity. Primary endpoints were objective response rate (ORR) and safety; secondary endpoints were duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Of 24 treated patients (pts), 19 had cervical and 5 had vaginal or vulvar cancer; median age was 51 y. At a median follow-up of 31 wks (range: 6–38), ORR was 20.8% (Table), and disease control rate (ORR + SD) was 70.8%. All responses were in pts with cervical cancer (ORR, 26.3%) and were observed regardless of PD-L1 or HPV status or number of prior R/M therapies. Median PFS was 5.5 mo (95% CI: 3.5, NR); median OS was NR. Conclusions: Nivolumab demonstrated encouraging clinical activity in pts with cervical cancer and a manageable safety profile in virus-associated GYN cancers, supporting further evaluation in these pts. Updated clinical and biomarker data to be presented. Clinical trial information: NCT02488759. [Table: see text]