bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiparametric prostate MRI and MRI/ultrasound fusion biopsy as tools to follow prostate cancer progression for men on active surveillance.
Authors: Shakir Nabeel , Walton-Diaz Annerleim , Rais-Bahrami Soroush , Turkbey Baris , Rothwax Jason , Hong Cheng William , Stamatakis Lambros , George Arvin , Okoro Chinonyerem , Raskolnikov Dima , Siddiqui Minhaj , Su Daniel , Simon Richard , Wood Bradford J. , Choyke Peter L. , Pinto Peter A.
Published: February 2017

63

Background: Active surveillance (AS) is an option for patients with low risk prostate cancer (PCa); however, determining disease progression is challenging. At the NCI, multiparametric MRI (MP-MRI) with our biopsy protocol (MR-US fusion-guided plus 12 core extended sextant biopsy) has been used to confirm eligibility for AS. We evaluated the utility of these modalities in monitoring patients on AS. Methods: Patients who underwent MP-MRI of the prostate with biopsy per our protocol between 2007-2012 were reviewed. We selected a subset who met Johns Hopkins criteria for AS (Gleason score≤6, PSA density≤0.15, tumor involvement of ≤2 cores, and ≤50% of any single core) by outside 12−core TRUS biopsy. Patients with Gleason score≤6 confirmed at first NCI biopsy session were followed with annual MP-MRI and biopsy. MRI progression was defined as an increase in MP-MRI suspicion level, lesion diameter, or number of lesions. Pathologic progression was defined as an increase to Gleason score≥7 in either 12-core or MR-fusion biopsy. We determined the association between MRI and pathologic progression. Results: 129 patients met JHU criteria for AS by outside biopsy. Mean age was 61.6 years and mean PSA 5.16ng/mL. 28/129 (21.7%) patients had Gleason score ≥7 at first NCI biopsy session.31 patients had at least two biopsy sessions (mean follow up 18 months, range 12-54 months) of which 9/31 (29%) increased in Gleason score, all to 3+4=7. Fusion biopsy detected more pathologic progression than did standard biopsy (Table). The positive predictive value of MP-MRI for pathologic progression was 50%, while the negative predictive value was 84%. The sensitivity and specificity of MP-MRI for increase in Gleason score was 67% and 73%, respectively. Conclusions: Stable findings on MP-MRI are associated with Gleason score stability in patients with low-risk PCa choosing AS. The majority of patients who had pathologic progression were detected on fusion biopsy, which may suggest that random biopsies are unnecessary in this population. Larger studies are needed to validate these findings. [Table: see text]
Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers to detect clinically significant disease: Results from the initial screening round of the IMPACT study.
Authors: Mikropoulos Christos , Castro Elena , Bancroft Elizabeth , Page Elizabeth , Taylor Natalie , Ahmed Mahbubl , Goh Chee Leng , Eeles Ros A. ,   IMPACT Collaborators
Published: February 2017

8

Background: Men with germline BRCA1/2 mutations have a higher risk of developing prostate cancer (PrCa) than non-carriers. IMPACT is an international consortium of 62 centers in 20 countries evaluating the use of targeted PrCa screening in men with BRCA1/2 mutations. This analysis reports the first year’s screening results for all men at enrolment in the study. Methods: We recruited men aged between age 40 and 69 with germline BRCA1/2 mutations and a control group that tested negative for a BRCA1/2 mutation. All men underwent prostate-specific antigen (PSA) testing at enrollment and those with a PSA of greater than 3ng/ml threshold were offered prostate biopsy. All men are offered a biopsy irrespective of PSA level after five years of screening. Results: We recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls) of whom 199 (8%) presented with a PSA greater than 3ng/ml. We performed a total of 162 biopsies and diagnosed 59 PrCas (18 BRCA1 carriers, ten BRCA1 controls; 24 BRCA2 carriers, seven BRCA2 controls); 66% of the tumors were classified as intermediate or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3·0ng/ml in BRCA2 mutation carriers was 48%, double that reported in population screening studies. A significant difference in detecting intermediate or high-risk disease was observed in BRCA2 carriers using this threshold. Conclusions: The IMPACT screening network will be useful for targeted PrCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this yields a high proportion of aggressive disease. Early data indicate that the majority of BRCA1/2 mutation carriers diagnosed with prostate cancer at biopsy had developed clinically significant disease (requiring radical treatment). Clinical trial information: NCT00261456.
Influence of one-year androgen deprivation therapy on lipid and glucose metabolism in patients with newly diagnosed prostate cancer.
Authors: Mitsuzuka Koji , Kyan Atsushi , Orikasa Kazuhiko , Fukushi Yasuo , Aoki Hiroshi , Narita Shintaro , Koie Takuya , Miyazato Minoru , Kakoi Narihiko , Arai Yoichi ,   Michinoku Japan Urological Cancer Study Group
Published: February 2017

87

Background: The adverse events of androgen deprivation therapy (ADT) are widely recognized, but ADT-induced alterations in lipid and glucose metabolism may be race-dependent. We prospectively recruited Japanese patients with newly diagnosed prostate cancer who underwent at least one year of ADT and examined changes in lipid and glucose metabolism in these patients. Methods: Patients with newly diagnosed prostate cancer were recruited between January 2011 and August 2012. Body weight, abdominal circumference, and blood testing results were recorded every three months, and visceral and subcutaneous fat were measured by computed tomography before and after one year of ADT. Results: One hundred three patients completed a one year course of ADT. Median age was 74 (range, 50 to 85). Thirty nine patients underwent ADT with luteinizing hormone-releasing hormone (LHRH) agonist monotherapy, while 64 patients underwent ADT with LH-RH agonist plus bicalutamide. Median prostate-specific antigen (PSA) before ADT was 16.7 ng/ml (range, 3.6-3316 ng/ml). Clinical stage was B (46.6%), C (28.2%), and D (25.2%). Mean increase in body weight, abdominal circumference and body mass index after one year of ADT was 3.8%, 4.1%, and 3.8%, respectively. Mean decrease of hemoglobin was 5.5%. Mean increase of total, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides was 9.0%, 10.8%, 5.0%, and 21.0%, respectively. Mean increase in fasting blood sugar and HbA1c was 4.6% and 1.7%, respectively. Changes in each variable from baseline to 0, 3, 6, 9, and 12 months was as follows: body weight, 0, 0.9, 2.7, 3.3, and 3.8%; hemoglobin, 0, 4.5, 3.7, 5.5, and 5.5%; total cholesterol, 0, 12.9, 11.4, 9.7, and 9.0%; triglycerides, 18, 26, 25, 21%; and HbA1c, 0, 2.1, 1.2, 1.2, and 1.7%. Increase of visceral and subcutaneous fat measured by computed tomography before and after one year of ADT was 32.4% and 35.4%, respectively. Conclusions: One year of ADT caused significant changes, especially in lipid metabolism, in Japanese patients with prostate cancer. Visceral and subcutaneous fat increased more than 30%. These changes were noticeable in the first half of the one year course of ADT. Appropriate monitoring and management of these patients is needed, because these changes might cause critical cardiovascular events. Clinical trial information: UMIN000004709.
A phase II study of 99mTc-trofolastat (MIP-1404) SPECT/CT to identify and localize prostate cancer in high-risk patients undergoing radical prostatectomy (RP) and extended pelvic lymph node dissection (EPLND) compared to histopathology: An interim analysis.
Authors: Slawin Kevin Mark , Ellis William J. , Tenke Peter , Joniau Steven , Alekseev Boris Y. , Buzogány Istvan , Mishugin Sergey , Klein Eric A. , Karnes R. Jeffrey , Scherr Douglas , Yuh Bertram E. , Jarrard David Frasier , Trabulsi Edouard John , Stolz Josef , Babich John , Youssoufian Hagop , Stambler Nancy , Armor Thomas , Israel Robert Joseph
Published: February 2017

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Background: Technetium (Tc99m) trofolastat (USANC) is a novel urea-based small molecule SPECT radiotracer with utility in imaging overexpression of PSMA in prostate cancer (PCa). Unlike earlier agents targeting PSMA, this ligand is rapidly internalized and retained in tumors. We conducted an open-label, multicenter phase 2 study in the US and Europe (NCT01667536). An interim analysis was performed at approximately 50% accrual. Methods: Patients (pts) with confirmed adenocarcinoma of the prostate scheduled for RP with EPLND at high risk for disease outside of the prostate gland were eligible. High risk pts were ≥cT3 or Kattan nomogram score ≥130. Within 30 days of screening, pts required a bone scan and pelvic MRI. After enrollment, pts received trofolastat followed by whole-body planar and SPECT/CT imaging 3 to 6 hrs later. Pts then underwent RP with EPLND within 21 days. SPECT/CT images were evaluated centrally by 3 readers blinded to clinical information and compared to on-site pathology assessments using a common scoring template. The primary endpoint was the ability of trofolastat to detect PCa within the gland. Secondary endpoints included detection of extent and location within the gland, pelvic lymph nodes and comparative performance against MRI. Results: 84 pts were enrolled to date from 16 centers. Interim data is available for 54 pts. A majority (≥2/3) of SPECT/CT readers correctly identified the presence or absence of primary PCa in 51/54 (94%, 85-98 95% CI) patients including 2 true-negative cases treated with neoadjuvant enzalutamide. Sensitivity and specificity were 94% (84-98 95% CI) and 100% (34-100 95% CI) respectively. Conclusions: Based on the interim data available, trofolastat has accurately detected primary prostate carcinoma within the gland with high sensitivity and specificity in high-risk pts prior to surgery. Updated results, analyses of secondary endpoints, pelvic lymph nodes, and comparative performance vs. MRI from this ongoing study will be presented. Clinical trial information: NCT01667536. [Table: see text]
Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040.
Authors: El-Khoueiry Anthony B. , Melero Ignacio , Crocenzi Todd S. , Welling Theodore Hobart , Yau Thomas Cheung , Yeo Winnie , Chopra Akhil , Grosso Joseph , Lang Lixin , Anderson Jeffrey , Dela Cruz Christine Marie , Sangro Bruno
Published: February 2017

LBA101

Background: Overexpression of PD-L1 in HCC has a poor prognosis. Safety and preliminary antitumor efficacy of nivolumab, a fully human IgG4 monoclonal antibody PD-1 inhibitor, was evaluated in a multiple ascending-dose, phase I/II study in patients (pts) with HCC. Methods: Pts with histologically confirmed advanced HCC with Child-Pugh (CP) score ≤ B7 and progressive disease (PD) on, intolerant of, or refusing sorafenib were enrolled. Dose escalation occurred in parallel cohorts based on etiology: no active hepatitis virus infection or virus-infected HCC pts. Pts received nivolumab 0.1 – 10 mg/kg intravenously for up to two years. The primary endpoint was safety. Secondary endpoints included antitumor activity using mRECIST criteria, pharmacokinetics, and immunogenicity. Results: The study has enrolled 41 pts with a CP score of 5 (n = 35) or 6 (n = 6), ECOG score of 0 (n = 26) or 1 (n = 15), 73% with extrahepatic metastasis and/or portal vein invasion, and 77% with prior sorafenib use. Eighteen pts remain on study, and 23 discontinued treatment due to PD (n = 17), complete response (CR; n = 2), drug-related adverse events (AEs; n = 2) and non-drug–related AEs (n = 2). Drug-related AEs of any grade occurred in 29 pts (71%; 17% grade 3/4), with ≥ 10% of pts experiencing aspartate aminotransferase (AST) increase and rash (each 17%), alanine aminotransferase(ALT) and lipase increase (each 15%), and amylase increase (12%). Grade 3 and 4 AEs ≥ 5% were AST increase (12%), ALT increase (10%) and lipase increase (5%). A dose-limiting toxicity occurred in an uninfected pt at 10 mg/kg; no maximum tolerated dose was defined in any cohort. Response was evaluable in 39 pts: 2 CR (5%) and 7 partial responses (PR; 18%). Response duration was 14–17+ months for CR, < 1–8+ months for PR, and 1.5–17+ months for stable disease (SD). Overall survival (OS) rate at 6 months is 72%. Conclusions: Nivolumab has a manageable AE profile and produced durable responses across all dose levels and HCC cohorts, with a favorable 6-month OS rate. Updated safety, antitumor activity, and biomarker data will be presented. Clinical trial information: NCT01658878. [Table: see text]
GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma.
Authors: Sehn Laurie Helen , Chua Neil Sun , Mayer Jiri , Dueck Gregory Scott , Trněný Marek , Bouabdallah Kamal , Fowler Nathan Hale , Delwail Vincent , Press Oliver W. , Salles Gilles A. , Gribben John G. , Lennard Anne , Lugtenburg Pieternella J. , Franklin Natalie , Wassner Fritsch Elisabeth , Fingerle-Rowson Guenter , Cheson Bruce D.
Published: February 2017

LBA8502

Background: Treatments are limited and outcomes poor in rituximab-refractory (Rit-Ref) iNHL. Bendamustine (B) has a 9 mo median PFS and 10 mo response duration in ph II trials. Obinutuzumab (GA101/Gazyva [G]) is a glycoengineered type II aCD20 mAb with activity and acceptable safety in Rit-Ref NHL. Methods: GADOLIN (NCT01059630) is a ph III open label study in pts with CD20+ Rit-Ref iNHL. In the B arm, pts received B 120 mg/m2 (d1+2, c1–6) alone; GB arm pts received B 90 mg/m2 (d1+2, c1–6) with G 1000 mg (d1, 8, 15 c1, d1 c2–6) for up to six 28d cycles. Non-PD GB pts then received G monotherapy every 2 mo for up to 2 yrs. Primary endpoint was PFS assessed by an independent radiology facility (IRF), with 80% power to detect 43% improvement in median PFS. Results: In the protocol specified interim analysis, 396 pts were randomized to receive B (n = 202 [198 treated]) or GB (n = 194). The IDMC recommended to unblind the study as the primary endpoint had been reached (4 Feb 2015). Baseline characteristics were balanced between arms. Median age was 63 yrs and pts had a median of 2 prior therapies. Median observation time was 20 mo (B) and 22 mo (GB). IRF-assessed median PFS was 14.9 mo (B) and not reached (NR) for GB (HR 0.55, 95% CI 0.4–0.74; p = 0.00011). Median investigator-assessed PFS was 14 mo for B and 29 mo for GB (HR 0.52, 95% CI 0.39–0.70; p < 0.0001). There were no significant differences in IRF-assessed ORR (63.0% B vs 69.1% GB) or CR (12.2% B vs 11.2% GB) at end of induction, in IRF-assessed best overall response up to 12 mo from start of treatment (76.6% B vs 78.6% GB), or in preliminary OS (median OS NR in either arm). In the treatment period, there were fewer Grade ≥ 3 adverse events with B than GB (62.1% B vs 68% GB), notably neutropenia (26.3% B vs 33.0% GB) and infusion-related reactions (3.5% B vs 8.8% GB), but more Grade ≥ 3 thrombocytopenia (16.2% B vs 10.8% GB), anemia (10.1% B vs 7.7% GB) and pneumonia (5.6% B vs 2.6% GB). Conclusions: G combined with B (90 mg/m2) followed by G maintenance significantly improved PFS vs B alone (120 mg/m2) in Rit-Ref iNHL. The clinically meaningful PFS improvement with GB is the first randomized evidence of benefit for a novel aCD20 mAb in Rit-Ref iNHL. Clinical trial information: NCT01059630.
Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius).
Authors: Lonial Sagar , Weiss Brendan M. , Usmani Saad Zafar , Singhal Seema , Chari Ajai , Bahlis Nizar J. , Belch Andrew , Krishnan Amrita Y. , Vescio Robert A. , Mateos María-Victoria , Mazumder Amitabha , Orlowski Robert Z. , Sutherland Heather J , Blade Joan , Scott Emma Catherine , Feng Huaibao , Khan Imran , Uhlar Clarissa M. , Ahmadi Tahamtan , Voorhees Peter Michael
Published: February 2017

LBA8512

Background: DARA, a human anti-CD38 IgG1κ mAb, has single agent activity and is well-tolerated in rel/ref MM (Lokhorst HM et al. ASCO 2014). This ongoing phase 2 study (NCT01985126) evaluated DARA monotherapy in the FDA breakthrough therapy designation population: MM patients with ≥ 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory to a PI and IMiD. Preliminary results are reported. Methods: MMY2002 is a 2-part, open-label, international, multicenter study. In part 1 stage 1, 34 patients were randomized to DARA 8 mg/kg (n = 18) q4w or 16 mg/kg (n = 16) qw x 8 wk, q2w x 16 wk, then q4w in a Simon-2-stage design to determine the most effective dose. Subsequently, 90 additional patients were enrolled in the 16 mg/kg DARA group. The primary endpoint was overall response rate (ORR) by independent review (IRC). Results: Data for the 16 mg/kg DARA group are presented (n = 106). Baseline characteristics: median time since diagnosis, 4.8 y; median prior treatment lines, 5; 75% ISS ≥ 2. Refractory to: last line of therapy, 96%; last PI and IMiD, 95%; pomalidomide, 63%: carfilzomib, 48%; alkylating agents, 78%. Adverse events (AE; ≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), cough (20.8%). Infusion-related reactions (IRR, 42.5%) were mainly grade 1/2 during first infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to IRRs; 5 (4.7%) discontinued treatment due to AEs. None of these AEs were assessed by the investigator to be DARA-related. ORR (IRC assessed) was 29.2%, with 3 sCR, 10 VGPR, and 18 PR with a 7.4 month median duration of response. ORR was consistent across clinically relevant subgroups. Median time to progression was 3.7 months. Median overall survival has not been reached and the estimated 1-year OS rate is 65%. After a median follow up of 9.4 months 14/31 (45.2%) of responders remain on therapy. Conclusions: In a heavily pre-treated MM population (95% refractory to last PI and IMiD), DARA at 16 mg/kg showed meaningful durable single agent activity, with deep responses and a favorable safety profile. Clinical trial information: NCT01985126.
Mammographic imaging after partial breast reconstruction: Impact of a bioabsorbable breast implant.
Authors: Harms Steven , Lebovic Gail , Kaufman Cary Steven , Cross Michael
Published: February 2017

111

Background: Marking the site of the excised tumor bed during partial mastectomy is critical for radiation targeting and surveillance for breast cancer recurrence. However, delineating the lumpectomy cavity margins is challenging, and dense fibrosis and scarring often present obstacles when reviewing post-operative mammograms for signs of early recurrence. To determine whether implantation of a "mini" breast implant used for partial breast reconstruction adversely affected post-operative breast imaging, we reviewed clinical imaging of 100 patients that had been implanted with a new bioabsorbable breast implant over a three year period. Methods: Following informed consent, 110 patients were implanted at the time of partial mastectomy with a bioabsorbable implant with a primary purpose of marking the surgical site of tumor excision for radiotherapy. In each case, the surgeon sutured the implant into the cavity at the location believed to be at greatest risk for recurrence. Implants were used for partial breast reconstruction, a guide for radiation treatment planning and routine mammographic follow-up. Mammograms were reviewed for implant visibility, presence of artifacts and other diagnostic criteria. Results: In all cases the implant was rated as easily visible on mammography and CT without appreciable artifact or interference with diagnostic capabilities. In addition, there was notably less dense fibrotic tissue visualized on mammographic imaging at the tumor excision site containing the implant. In some cases, the marker clips coalesced in the center of the surgical cavity. The marker was also seen on US and MRI during routine follow-up. Conclusions: Mammographic imaging in patients implanted with this new device was not adversely affected by its presence. The implant visually assisted with verification of the excised tumor bed without introducing any artifact or diagnostic interference and there was notable in-growth of normal breast tissue clearly seen on mammography. In this group of patients there were no abnormal calcifications in or around the implant and there were no recurrent cancers detected within this 36 month period.
Predictive and prognostic value of tumor-infiltrating lymphocytes in breast cancer treated with neoadjuvant chemotherapy.
Authors: Matsumoto Akiko , Jinno Hiromitsu , Hiraiwa Kunihiko , Nakamura Tetsuya , Saito Junichi
Published: February 2017

128

Background: The prognostic importance of tumor-infiltrating lymphocytes (TILs) in triple-negative (TN) and HER2-positive breast cancer has been suggested in recent trials. The aim of this study is to evaluate a relationship between TILs and response to neoadjuvant chemotherapy (NAC) as well as long-term outcome in breast cancer including luminal, TN and HER2 subtypes. Methods: Twenty-seven patients receiving NAC from January 2010 to March 2015 at Inagi Municipal Hospital were analyzed. Intratumoral lymphocytes (ItuLy) and stromal lymphocytes (StrLy) were evaluated in hematoxylin and eosin-stained sections from pretherapeutic core needle biopsies. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors with > 50% of ItuLy or StrLy. Results: A total of 27 patients were divided into 13 luminal (48.1%), 3 TN (11.1%) and 11 HER2 (40.7%) subtypes. The median age was 58 years and the median tumor size was 3.0 cm. A significant correlation between ItuLy (the median percentage: 5%) and StrLy (25%) was observed (Pearson correlation coefficient = 0.628, P< 0.01). LPBC comprised 29.6% (8/27) of total population, with higher frequencies of 33.3% and 54.5% in the TN and HER2-positive subtypes, when compared with 7.7% in luminal subtype (P= 0.044). LPBC group had a significantly higher pathological complete response (pCR) rate of 62.5% (5/8), compared with 5.3% (1/19) for non-LPBC group (P= 0.004). LPBC showed the modest correlation with pCR in luminal (100% (1/1) vs. 0% (0/12), P= 0.077) and HER2-positive subtypes (66.6% (4/6) vs. 25% (1/5), P= 0.175). In TN subtype, neither LPBC nor non-LPBC showed pCR. After a median follow-up of 24.3 months, patients with any TILs were significantly associated with better disease-free survival (DFS) than those without TILs (24.3 vs. 23.6 months, P= 0.016). The most significant impact of TILs on DFS was observed in HER2-positive subtype (23.2 vs. 15.2 months, P= 0.046), whereas TILs did not associate with DFS in luminal and TN subtypes. Conclusions: The presence of TILs was a significant predictor for response to NAC and would provide useful information of prognosis in breast cancer.
Next-generation sequencing (NGS) in metastatic breast cancer (mBC) patients: Translation from sequence data into clinical practice.
Authors: Moreira Raphael Brandao , Peixoto Renata , Sousa Tercia Tarciane Soares de , Cruz Marcelo , Maluf Fernando , Buzaid Antonio
Published: February 2017

133

Background: A considerable number of patients with mBC progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with the use of a NGS platform in refractory mBC and its clinical utility. Methods: We retrospectively reviewed demographics, NGS results, and the suggested therapies received by patients undergoing NGS (Foundation Medicine, Cambridge, MA, USA): exonic sequencing of 315 genes and selective intronic sequencing from 28 genes for refractory mBC. Co-primary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage of them who received genotype-directed therapy. Results: Samples from 20 patients were tested. Histologic subtype consisted of triple negative (50%), HER 2 +, hormonal receptor [HR] - 15%, HR + and HER 2 - (35%). A targetable genomic alteration was identified in 14 (70%) patients, most frequently in TP53 (11 [55%]), PIK3CA (8 [40%]), FGFR1 (4 [20%]), CCND1 (3 [15%]), PTEN (3[15%]) and BRCA2 (2[10%]). Therapy could be personalized in 9 (45%) of 14 patients. Of the 9 patients who were received targeted therapy, 7 (77%) had an objective response and had stable disease for more than 3 months. Conclusions: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in the majority of advanced breast cancer patients. The assay provided clinical benefit in 35% of the patients.
uPA receptor and its interaction partners: Impact as potential therapeutic targets in triple-negative breast cancer.
Authors: Aubele Michaela , Huber Michaela Christina , Falkenberg Natalie , Gross Eva , Braselmann Herbert , Walch Axel Karl , Schmitt Manfred
Published: February 2017

150

Background: Triple-negative breast cancers (TNBC), which lack expression of estrogen (ER), progesterone (PR), and HER2 receptors are characterized by tumor tissue expression of the urokinase-type plasminogen activator receptor (uPAR) system. Methods: We evaluated uPAR and its interaction partners (uPAR-interactome) by immunohistochemistry (IHC) in tissue microarrays (TMA) prepared from ~300 TNBC tumor tissue specimens and in the TNBC model cell lines BT549 and MDA-MB231. Protein expression of 25 different factors constituting the uPAR-interactome was evaluated by IHC; several of the uPAR-protein complexes were identified employing the proximity ligation assay (PLA). Results were correlated with histomorphological parameters and survival of the patients. RNA interference was employed in the TNBC cell lines for several of the parameters assessed. To analyze effects of uPAR and/or uPA depletion on malignant cell behavior, proliferation, migration, and invasion assays as well as Western blot, PLA, immunoprecipitation, mass spectrometry, and immunohistochemistry were conducted. Results: After downregulation of uPAR and uPA in TNBC cell lines, significantly reduced cell proliferation, invasion, and migration were observed. Furthermore, interaction between uPAR and IGF1R (insulin-like growth factor1 receptor) was shown, and several novel interaction proteins of uPAR could be identified, such as Cyr61 (cysteine-rich angiogenic inducer61). In TNBC tumor specimens, association between uPAR expression and histological grade plus expression of cathepsin B, IGF1R, IR (insulin receptor), and plasminogen was shown. Expression of KLK4 (stromal) and Ki67 was correlated with disease-free survival of the patients. Presence of uPAR/IGF1R protein complexes was associated with histological grade, with the expression of PAI-1, Ki-67, p27, and cathepsin B. Conclusions: Our findings demonstrate that uPAR and its interacting partners, expressed in TNBC tumor tissues, may be considered as potential novel therapeutic targets for this fatal disease.
Age, race, BMI, and pathologic complete response following neoadjuvant chemotherapy: An analysis of four alliance clinical trials.
Authors: Warner Erica T , Ballman Karla V. , Buzdar Aman , Carey Lisa A. , Sikov William M. , Strand Carrie , Partridge Ann H.
Published: February 2017

33

Background: Pathologic complete response (pCR) is an important prognostic indicator and surrogate endpoint, particularly for patients with hormone receptor-negative breast cancer. Previous studies have suggested differential response to pre-operative therapy by age and body mass index (BMI), though no association has been seen by race. We assessed associations of age at diagnosis, BMI and race with pCR accounting for breast cancer subtype. Methods: Women enrolled in four clinical trials of neoadjuvant chemotherapy (CALGB 40601 and 40603; ACOSOG Z1031 and Z1041) were eligible for this analysis. Age, race, and BMI were abstracted from patient records at baseline. Tumor subtype was assessed using immunohistochemical staining and/or fluorescence in situ hybridization. Logistic regression models were used to determine the association of race/ethnicity and age at diagnosis with pCR, the absence of residual invasive disease in the breast after neoadjuvant chemotherapy, adjusting for subtype (HER2+, ER+/ HER2-, triple negative), age, study arm, lymph node status, tumor size, and tumor grade. Results: 1,146 women with a mean age of 51.5 years were included. 156 (13.6%) were of black race. 590 (51.5%) of tumors were HER2+, 169 (14.7%) were ER+/HER2- and 387 (33.8%) were triple negative. In multivariate analyses controlling for tumor characteristics and other factors, black race (OR: 1.07, 95% CI: 0.67-1.70), age (OR: 0.99, 95% CI: 0.97-1.00) and BMI (OR: 0.99, 95% CI: 0.96-1.01) were not significant predictors of pCR. Similar associations we observed when stratified by subtype, and we found no interaction between age and black race (p=0.06), black race and BMI (p=0.54) or age and BMI (p=0.73). Conclusions: After accounting for tumor characteristics, we observed no differences in pCR rates according to race, age or BMI.
Concordance of Van-Nuys Prognostic Index, Memorial Sloan Kettering Breast Cancer nomogram and Oncotype Dx DCIS scores in prediction of ductal carcinoma in situ(DCIS) recurrence risk.
Authors: Matlock Kinzie , Lloyd Jillian M. , Carter W. Bradford , Grujic Edina , Frazier Thomas G.
Published: February 2017

56

Background: Ductal Carcinoma in situ (DCIS) has a wide spectrum of bioagressiveness. Three models used to assess recurrence risk (RR) of DCIS include: the Van-Nuys Prognostic Index (VN), Memorial Sloan Kettering Breast Cancer Nomogram (MN) and Oncotype Dx DCIS Score (OD; Genomic Health, Redwood City, CA). The aim of our study was to evaluate the concordance between these RR models. Methods: An IRB-approved retrospective chart review was performed on 37 consecutive patients at our institution with DCIS from 12/2011-4/2015 who underwent breast conservation surgery and in whom an OD was obtained. The OD and ‘any recurrent event at 10-years’ scores were used to stratify patients into low risk (LR; OD DCIS score <39/<17%), intermediate risk (IR; 39-54/17-24%) and high risk (HR; >54/>24%), as outlined in the original OD study. The ‘10-year RR’ scores from MN were stratified using the same percentile breakdown as OD. The VN were stratified into LR (4-6), IR (7-9) and HR (>9) groups based on the updated VN study’s guideline. Pathologic slides were re-reviewed by one pathologist blinded to OD score to determine size and margin width based on the protocol outlined in the original VN paper. The three scores for each patient were compared. Results: Eleven patients (29.7%) had concordance between all three scores and all were LR. In 10.8% of patients, there was no concordance between the three scores. The concordance between the OD and VN, OD and MN, and VN and MN was 64.9%, 48.6% and 35.1%, respectively. Conclusions: In evaluating RR, determining LR may have the greatest implication since this group may be the least likely to benefit from adjuvant radiotherapy. Concordance between all three models was seen only in LR patients. All patients who were LR by VN were also LR by OD and MN. Determining a VN initially may help guide additional testing. The added value of OD may be primarily in patients who are not LR by VN. The MN seems to be of limited value in this study. Larger studies assessing these relationships and their outcomes in predicting potential RR in DCIS are warranted.
Development of a new photonumeric scale for acute radiation dermatitis in patients with breast cancer.
Authors: Shumway Dean , Walker Eleanor M. , Kapadia Nirav S. , Do Thy Thy , Griffith Kent A. , Feng Mary Uan-Sian , DePalma Bonnie , Helfrich Yolanda R. , Gillespie Erin , Miller Alexandria , Jagsi Reshma , Pierce Lori J.
Published: February 2017

86

Background: The Common Terminology Criteria for Adverse Events (CTCAE) is frequently used to grade the severity of acute radiation dermatitis (ARD), but has not been validated despite decades of clinical use. We sought to develop a photonumeric scale to consistently describe ARD in breast cancer patients undergoing radiation (RT). Methods: Patients enrolled on a prospective study that included photographs and quantitative measurements of erythema and hyperpigmentation using colorimetry. 209 photographs from 35 patients with white skin and 369 photographs from 50 patients with skin of color were used to develop two photonumeric scales. Predominant erythema (in white skin) OR hyperpigmentation (in skin of color) were rated on a 4 point scale, with grading of desquamation on a separate 3 point scale. Four raters used both CTCAE and photonumeric scales to independently score all photographs. Intra- and inter-rater agreements were assessed using weighted kappa scores. Results: Using the CTCAE, 95% of photos were rated as grade 1 or 2. There was a trend toward higher grade in patients with skin of color, with grade 2 toxicity in 43% vs. 24%. Intra-rater agreement for CTCAE ratings was 65—87% (kappa 0.34—0.67), with a wide range of inter-rater agreement (56—81% agreement fraction, kappa 0.04—0.58). Using the photonumeric scale, intra-rater agreement was high for erythema/hyperpigmentation in patients with white skin (74—82%, kappa 0.49—0.70) and skin of color (69—86%, kappa 0.55—0.79), along with desquamation (78—87%, kappa 0.52—0.66). There was moderate inter-rater agreement for erythema/hyperpigmentation (51—82%, kappa 0.15—0.71) and desquamation (63—88%, kappa 0.36—0.58). Colorimetric measurements correlated strongly with photonumeric grade. Conclusions: We report a new photonumeric scale for ARD in breast cancer patients with satisfactory reliability across the spectrum of skin pigmentation. Intra-physician ratings were consistent, with moderate inter-physician agreement. The CTCAE functions as a binary scale, with 95% of ARD rated as grade 1 or 2 toxicity. Future work includes correlation with patient-reported outcomes and physician ratings at the point-of-care. Funded by a Munn Idea Grant (G011480).
Encouraging regular physical activity for hormone-receptor positive breast cancer patients to improve mental and physical health during treatment and survivorship.
Authors: Jordan Corinne , Klepsa Alicia
Published: February 2017

91

Background: Physical inactivity has direct effects on risk of chronic diseases, mental health, quality of life, and early mortality. Women that engage in physical activity after a breast cancer diagnosis may reduce the risk of recurrence and death from this disease. This study examines postmenopausal women with clinical stage I or II breast cancer using the Patient Reported Outcome Measurement Information System (PROMIS) 10 – Global Health Survey, Fitbit Flex, and regular Wellness Coaching. Methods: Our prospective study follows clinical stage I/II, postmenopausal, ER+, Her2- women with BMI > or = to 25 beginning at their surgical consultation. Visits occur again post-operatively, six months after consultation, and again at one year. Each patient was given a Fitbit Flex with the expectation to complete 7,000 steps daily, and weekly Wellness Coaching. At each visit, a record of their activity was recorded including steps, heartrate, blood pressure, and body mass index. Quality of life was also assessed using PROMIS 10 - Global Health Survey. Results: 19 patients have enrolled. 100% of patients on study had BMI stay the same or decrease from initial consult to postop visit. 66% gained weight from initial postop visit to 6 months. 47% of patients met the daily goal of 7,000 steps. 80% showed significant increase in mental health scores and 60% increased physical health scores by PROMIS 10. Conclusions: Encouraging regular physical activity during treatment and survivorship for breast cancer can improve mental health and physical well-being during breast cancer treatment. Regular wellness coaching can support patients to reach their physical and mental health goals during treatment and survivorship.
3 Steps 4 Health, a program on quality of life.
Authors: Fonfa Ann
Published: February 2017

95

Background: As Patient advocates we have spent years gathering/ sharing information about simple, natural strategies to reduce risk of cancer treatment-related toxicities and strengthen the immune system. Methods: We created a simple 3 step program that absolutely anyone with cancer, at any stage, can incorporate into their own healthful protocol. Since it involves no tools and can be used at the level that an individual is at the time they start, we consider it appropriate for all. Further we cannot see any objection from the Oncologist or staff members. Step 1 is eating one more fruit and one more vegetable every day. This is helpful since studies show few Americans are getting enough fruits or vegetables. The National Cancer Institute considers ‘Five a Day’, a minimum. We want to get people started on the correct path simply and easily. Step 2 is taking a walk around the room, facility or neighborhood depending on ability and health status. This has been shown by many studies to help anyone with cancer, undergoing treatment or in recovery. We are not asking folks to become athletes; we are involving them in a plan to improve their health. Step 3: 7 deep breaths before treatment, in a stressful situation or at bedtime. This step is important to reduce stress and encourage relaxation. Results: Every step moves people forward into better health. We believe taking these first steps will lead to more healthful behaviors, better ability to handle conventional cancer treatments, and an easier recovery. Conclusions: Immune system health depends on the individual as much as any treatments. In this era of Immunology, we see a real opportunity for our Patient/Advocate-driven concept.
Symptom burden in hospitalized patients with advanced cancer.
Authors: Moran Samantha M.C. , El-Jawahri Areej , Pirl William F. , Traeger Lara , Kumar Pallavi , Ryan David P. , Lennes Inga Tolin , Cashavelly Barbara J. , Martinson Holly S , VanDusen Harry , Hochberg Ephraim P. , Jackson Vicki A. , Greer Joseph A. , Temel Jennifer S. , Nipp Ryan David
Published: February 2017

100

Background: Patients with advanced cancer experience high rates of both physical and psychological morbidity, but data describing patients’ symptoms during hospital admissions are lacking. We sought to describe symptom burden in hospitalized patients with incurable solid and hematologic malignancies. Methods: We prospectively enrolled patients with incurable cancers admitted to the Massachusetts General Hospital from 9/1/2014 through 5/1/2015. Within the first week of their admission, we assessed physical and psychological symptoms using the Edmonton Symptom Assessment System-revised (ESAS-r). Beginning 11/15/2015, we also administered the Patient Health Questionnaire 4 (PHQ-4), scored categorically. Results: We enrolled 457 of 547 (84%) eligible patients. Participants (mean age=63.8 years; n=231, 51% female) had the following malignancies: gastrointestinal (n=149, 33%), lung (n=77, 17%), genitourinary (n=52, 11%), breast (n=33, 7%), hematologic (n=24, 5%), and other solid tumors (n=122, 27%). Using the ESAS-r, tiredness, drowsiness, anorexia, and pain were the most common severe symptoms. Using the PHQ-4, approximately one-third of participants screened positive for depression (91/271, 34%) and anxiety (86/273, 32%). Conclusions: Hospitalized patients with incurable solid and hematologic malignancies experience substantial physical and psychological symptoms. Most patients reported at least moderate tiredness, drowsiness, anorexia and pain. Additionally, a concerning proportion reported depression and anxiety. Our data demonstrate the need for efforts to alleviate the physical symptoms experienced by this population, while also seeking to understand and address their psychological needs. [Table: see text]
How do palliative care needs vary across the disease trajectory in patients with gynecologic cancer?
Authors: Ruskin Rachel , Rowland Michelle Renee , Moore Katherine N , Lefkowits Carolyn , Walter Adam , Slaughter Katrina , Landrum Lisa Michelle , Walker Joan L. , Matzo Marianne
Published: February 2017

106

Background: The WHO’s integrated model emphasizes that palliative care (PC) should be provided concurrently with curative and life-prolonging care, with disease-directed treatments decreasing and PC increasing over time. This study aimed to understand how accurately this theoretical model matches the PC needs of gynecologic cancer (GC) patients. Methods: GC patients at a comprehensive cancer center completed a symptom and needs assessment questionnaire as part of routine care. Needs were divided into physical, emotional, social, practical, and informational domains. Patients reporting at least one symptom score ≥ 4/10 made the physical need domain positive. For the remainder of the categories, patients endorsing at least one need in a given domain made that domain positive. Time points in the illness trajectory were categorized as diagnosis, primary treatment, remission, and progression/recurrence. Univariate analyses were utilized to assess differences in needs at various time points. Results: Questionnaires from 1348 patient visits over 3 months were included. Patients had ovarian (39%), uterine (36%), cervical (16%), and vulvar (5%) cancer. Visits occurred around the time of diagnosis (6%), during primary therapy (28%), during remission (42%), and during disease progression or recurrence (23%). Physical needs were most common at diagnosis and during progression/recurrence (p < 0.01). Emotional needs (p < 0.01), social needs (p < 0.01), and informational needs (p < 0.01) all varied throughout the course of disease and were highest at diagnosis. At each time point, at least 65% of patients had one or more PC needs. Having needs in multiple domains ( ≥ 3) was associated with time point, with patients around the time of diagnosis having the highest rate of need in multiple domains (p < 0.01). Conclusions: GC patients have a broad range of PC needs across the trajectory of their illness. The WHO schema fails to capture the full scope of these needs and under-appreciates their prevalence earlier in the course of the disease. These results underscore the importance of training gynecologic oncologists in primary PC as well as increasing referrals to specialist PC providers.
The acceptability to African-Americans of a structured conversation guide to improve advance care planning in the setting of cancer: A focus-group study.
Authors: Sanders Justin J , Sterba Katherine W. , Ford Dee , Block Susan
Published: February 2017

11

Background: African-Americans are less likely than whites to participate in advance care planning (ACP), which may contribute to disparities in the receipt of goal-concordant care. Literature points to multiple factors: the impact of religion, mistrust, different preferences for life-sustaining measures, family-decision making styles and poor knowledge about ACP. Early ACP conversations are associated with improved outcomes at the end of life, including goal-concordant care. A systematically-developed, serious illness conversation guide (“guide”) for oncologists, embedded in a systems-based approach to improving illness care, has demonstrated more frequent, higher-quality, and earlier ACP conversations in a predominantly white and middle class cohort of cancer patients. This study aimed to explore the acceptability and need for modification of the guide in more diverse populations. Methods: We conducted a series of focus groups with panels of clinicians and researchers, African-American church members, and seriously ill patients and their caregivers to assess barriers to ACP and preferences concerning modifications to the guide. We used template analysis to code themes at the individual, interpersonal and systems levels. Results: At the individual level, participants confirmed the importance of religion and the impact of perceived discrimination (e.g., receipt of inferior care) and superstition (e.g., talking about death may make it happen). Interpersonal-level factors influencing ACP included family, trust, and concerns about provider abandonment. Participants confirmed systems-level barriers of access and mistrust in the healthcare system and highlighted community outreach as a key part of the process. Participants reported positive responses to the tone and content of the guide and found the guide to be acceptable when it included a question that elicited coping mechanisms, including religion. Conclusions: Participants in our study found the use of a serious illness conversation guide to identify patient goals and priorities acceptable, and emphasized the importance of adding a question focused on coping and religion.
Site of death, place of care, and burdensome transitions among patients with advanced solid tumor malignancies or leukemia between 2000 and 2010.
Authors: Prsic Elizabeth Horn , Teno Joan M. , Gozalo Pedro
Published: February 2017

144

Background: Early palliative care has been associated with improved outcomes in oncology patients. However, there is limited data on end-of-life (EOL) care in hematology patients over time. We describe site of death, place of care, and transitions at the EOL among leukemia and advanced solid tumor malignancy (ASTM) patients. Methods: Retrospective cohort study of fee-for-service Medicare beneficiaries 66 years and older who died in 2000 (n = 40,805) and 2010 (n = 43,547) with leukemia or advanced lung, colorectal, or pancreatic cancer. Based on Medicare billing data, we identified site of death, place of care, and burdensome transitions (BT). Examples of BT include multiple hospital admissions for expected complications, referral to hospice in the last 3 days of life (DOL), and EOL transfers. Results: The rate of acute hospital death decreased for leukemia and ASTM patients over time (adjusted rate decreases 8.4% in leukemia vs. 8.2% in ASTM, p < .001). However, acute hospital death was more likely in leukemia patients in 2010 (adjusted rates 35.8% vs. 19.0% in ASTM, p < .001). Intensive care unit (ICU) admission in the last 30 DOL increased in both groups, and was more likely in leukemia patients in 2010 (adjusted rates 34.2% vs. 23.4% in ASTM, p < .001). Transitions in the last 3 DOL increased over time, and occurred more frequently in leukemia patients compared to ASTM patients in 2010 (adjusted rates 24.5% vs. 19.0% in ASTM, p < .001). Multiple admissions for expected complications increased similarly for patients in both groups over time (adjusted rate increases 2.7% in leukemia vs. 2.9% in ASTM, p < .001). There was a striking increase in freestanding hospice inpatient unit care before death over time (increasing from 4.5% to 11.5% in leukemia and 7.5% to 15.9% in ASTM). Conclusions: Between 2000 and 2010, the rate of acute hospital death decreased in both leukemia and ASTM patients. However, there were increased rates of ICU and multiple admissions for expected complications in both groups, particularly in leukemia patients compared to ASTM patients. A similar increase was also observed in the use of freestanding hospice units before death for both groups.