bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of neoadjuvant combination immunotherapy in locally/regionally advanced melanoma.
Authors: Najjar Yana , McCurry Dustin , Lin Huang , Lin Yan , Davar Diwakar , Drabick Joseph J. , Neves Rogerio Izar , Ernstoff Marc S. , Puzanov Igor , Skitzki Joseph J. , Pingpank James F. , Holtzman Matthew Peter , Sander Cindy , Rose Amy , Kirkwood John M. , Tarhini Ahmad A.
Published: May 2019

9586

Background: A trial of neoadjuvant pembrolizumab (P) in combination with high dose interferon-α (HDI) in high-risk patients (pts) with locoregionally advanced melanoma (mel) has completed enrollment. Methods: Primary endpoint: safety of combination P-HDI. Pts were treated with P x 2 doses followed by definitive surgery, then x1 year. HDI was given concurrently, and both agents were per standard regimen. Tumor and blood samples were obtained at baseline and at surgery (wk 6-8), blood at 6 wks, 3,6,12 months (mos). Results: 30 pts were treated (22 male, 8 female, age 26-83). 16 had cutaneous primary, 3 mucosal, 11 unknown. At enrollment, 16 had recurrent disease, 6 received prior adjuvant therapy with ipilimumab (4) or HDI (2). 16 had AJCC 7 stage IIIB, 9 IIIC, 5 IV. 332 P cycles have been delivered (median 13), 496 doses of HDI induction (median 17), 1329 doses of HDI maintenance (median 44). HDI was dose reduced in 20 pts, discontinued in 27, P discontinued in 8. Radiologic preoperative RR was 77% (95% CI, 59-88) (6 CR, 17 PR). 20% (6) had SD and 1 had PD. All pts underwent definitive surgery. The pathologic complete response (pCR) of 26 pts was 32% (95% CI, 18-51). 6 pts recurred and 3 died. No pt with pCR has recurred. Median f/u time is 17.4 mos, median PFS/OS not reached. Most common grade (Gr) 3 toxicities: hypophosphatemia (10; 33%), fatigue (10; 33%), ↑CPK (6; 20%), ↑lipase (4; 13%). 3 Gr 4 events (↑CPK, hyperglycemia, lymphocyte count decreased). 1 suspected grade 5 event occurred 6 months after completion of therapy. PD-L1 expression at baseline did not correlate with clinical outcomes. In 8 pts with pre and post treatment tumor samples, IHC expression of PD-1, PD-L1, CD11b, CD8, Foxp3 and CD25 increased post-treatment (p < 0.05). Conclusions: Neoadjuvant P-HDI has promising clinical activity, although treatment is limited by HDI toxicity. Treatment increases the immune cell infiltrate, and outcomes do not correlate with baseline expression of PD-L1. Longer follow up and further mechanistic studies are underway. Clinical trial information: NCT02339324.
Challenges in sentinel node (SN) pathology in the era of adjuvant treatment: The risk of over and undertreatment stress the need for expert pathology review.
Authors: Franke Viola , Madu Max Fullah , Bierman Carolien , Klop Willem M.C. , van Houdt Winan J. , Wouters Michel W.J.M. , Van De Wiel Bart A. , Van Akkooi Alexander Christopher Jonathan
Published: May 2019

9593

Background: With the approval of adjuvant therapy for stage III melanoma, accurate staging in melanoma patients is important more than ever to prevent over- or undertreatment. Sentinel node biopsy (SNB) is an accurate staging tool, yet the presence of capsular nevi (CN) can lead to a false positive diagnosis. We compared positive SNB and CN patient outcomes and aimed to evaluate the cause of false positive SNB and discern diagnostic pitfalls in their evaluation. Methods: Retrospective analysis of AJCC 7th Edition stage IIIA melanoma patients (N1-2a, non-ulcerated primary tumor) who were treated at our institute between 2000 and 2015. SNB slides were reviewed for this study by an expert melanoma pathologist. Baseline characteristics were assessed for SN+ and CN+ patients. Concordance rates for SNB evaluation before and after revision were documented and diagnostic pitfalls were discerned. Results: 169 patients were diagnosed, 10 could not be reviewed due to lack of evaluable slides. Of these 159 cases, 14 patients originally diagnosed with metastatic melanoma were shown to have capsular nevi (8.8%). Another 2 patients were shown to have melanophages that were incorrectly interpreted as metastases (1.3%). Thus, 10.1% was considered false positive after revision. In 14 patients the SN tumor burden was originally reported > 1 mm, but turned out to have < 1 mm SN tumor burden. 4 patients originally reported as SN tumor burden < 1 mm before revision turned out to have > 1 mm SN tumor burden. These 32 patients (20%) might have potentially been over- or undertreated in the current era of adjuvant therapy for stage III melanoma. Conclusions: False positive sentinel node results in melanoma are real, they can occur for a number of reasons, but distinguishing metastatic melanoma from benign capsular nevi and melanophages can be a diagnostic challenge. We plead for an expert pathologists’ review in any case, but certainly when using the SNB+ results to determine treatment consequences for SN+ melanoma patients.
tRNA-derived small RNA fragments (tRFs) as potential biomarkers for doxorubicin resistance in breast cancer.
Authors: Wu Xiaowei , Fu Ziyi , Ge Han , Liu Xiaoan , Xia Yiqin , Li Minghui , Huang Yue , Peng Jinhui , Wang Shui , Xie Hui
Published: May 2019

e12000

Background: It has been confirmed that tRNA-derived small RNA fragments (tRFs) participate in various kinds of biological activities. However, the function of tRFs in chemotherapy resistance in breast cancer still remains unclear. The purpose of this study is to elucidate the relation between tRFs expression character and chemotherapy resistance in breast cancer. Methods: Drug sensitivity was validated by using Cell Counting Kit-8 in ADR-sensitive breast cancer cells (MCF-7) and ADR-resistant cells (MCF-7/ADR). Next-generation sequencing technology was conducted to identify differentially expressed tRFs between MCF-7 and MCF-7/ADR breast cancer cell lines; quantitative RT-PCR (qRT-PCR) were used to validate the differentially expressed tRFs in MCF-7 and MCF-7/ADR cell lines and the serums of chemotherapy sensitive and resistant patients. Then the dysregulated tRFs were identified through Gene ontology (GO), Pathway analysis and network analysis. Finally, receiver operated-characteristic curve (ROC) analysis was carried out to assess the predictive power of the dysregulated tRFs as biomarkers for chemotherapy resistance.The growth and sensitivity of breast tumor to Adriamycin were assessed by micro-CT in vivo. Results: There were 588 differentially expressed tRFs between MCF-7 and MCF-7/ADR cell lines (fold change > 2).tRF-2023, which was significantly downregulated in chemotherapeutic resistance breast cancer tissues and cells, could induce the sensitivity of breast cancer cells to Adriamycin both in vivo and in vitro. Bio-informatic analysis showed that tRF-2023 was mainly involved in flavonoid glucuronidation and cellular gluuronidation, and the target genes of tRF-2023 were involved in RNA polymerase, purine and pyrimidine metabolism, and p53 signaling pathway, which might illuminate the function of tRF-2023 in chemotherapy resistance of breast cancer. The result of ROC also showed that tRF-2023 was involved in breast cancer resistance. Conclusions: Our study provides a comprehensive analysis of tRFs in breast cancer resistance. It is helpful in revealing the significance of tRFs during the development of chemotherapy resistance in breast cancer. We also identified that tRF-2023 could be a new potential biomarker and therapeutic target for chemotherapy-resistant breast cancer.
Pharmacokinetic (PK) characterization of irinotecan liposome injection in patients (pts) with metastatic breast cancer (mBC).
Authors: Anders Carey K. , Sachdev Jasgit C , Munster Pamela N. , Pedret-Dunn Anna , Maxwell Fiona , Northfelt Donald W. , Han Hyo S. , Ma Cynthia X.
Published: May 2019

e12003

Background: Irinotecan liposome injection (nal-IRI) uses intraliposomal stabilisation technology to enable high drug load and in-vivo stability. This analysis characterizes the PK profile of nal-IRI in pts with mBC. Methods: The expansion of NCT01770353 enrolled 30 pts with mBC over three cohorts (Cohort 1: ER+ and/or PR+ BC [C-1]; Cohort 2: Triple Negative BC [C-2]; and Cohort 3: BC with active Brain Metastasis [C-3]). Key inclusion criteria: ECOG ≤1; adequate organ function; and >1 and ≤5 prior lines of cytotoxic therapy in metastatic setting. Most pts received nal-IRI 60 mg/m2 salt-based equivalent (50 mg/m2 free base equivalent [FBE]) or 80 mg/m2 (70 mg/m2 FBE) q2w by iv infusion, based on tolerance; 2 pts were treated at 40 mg/m2 (35 mg/m2 FBE). Plasma samples were collected over 360h across cycles 1, 2 &3, and analysed using LC-MS/MS for total irinotecan. Data were analysed by a non-compartmental approach using Phoenix Winnonlin, and were compared with values from studies in other tumor types. Results: 21 patients were evaluable for PK analysis (C-1, n=6; C-2, n=7; and C-3, n=8). No trend for accumulation was observed in cycle 2 or 3, when comparing total irinotecan Cmax & exposure (area under the curve at 168 h [AUC168]) versus cycle 1. At 40-80 mg/m2 (35-70 mg/m2 FBE), Cmax of irinotecan tended to increase proportionally with total dose, and was comparable to studies in other tumour types (see Table). Among 29 pts who received nal-IRI, partial response (per RECIST) was observed in 10 pts. The most related TEAEs (≥ 25%) were diarrhea, nausea, vomiting, hypokalaemia, decreased appetite and fatigue. Stable disease was observed in 5 pts. Conclusions: PK parameters in patients with mBC were comparable to historical studies in patients with other tumour types. The safety profile of nal-IRI monotherapy appeared consistent with gastrointestinal and blood disorders. [Table: see text]
A prognostic nomogram to predict the benefit of adjuvant radiotherapy for resected inﬂammatory breast cancer patients.
Authors: Ping Yang Jun , Nan Qian Chao
Published: May 2019

e12007

Background: A nomogram is a convenient and reliable tool for individualizing cancer prognosis. Therefore, the purpose of this study was to construct a clinical nomogram for predicting overall mortality (OM) to help clinicians to make individualized estimates of the potential benefit of adjuvant radiotherapy (RT) for resected inﬂammatory breast cancer (IBC) patients. Methods: We used the Surveillance, Epidemiology, and End Results database to identify 4030 IBS patients treated with surgery between 2004 and 2012, and randomly classified the patients into the discovery (n = 2417) and validation (n = 1613) cohorts. A Cox regression hazards model was used to build a nomogram by determining the prognostic factors for OM in the discovery cohort. The overall accuracy and discriminative ability was measured by Brier score and Harrell's concordance index (c-index). Results: In multivariate analysis, age, race, number of primaries, N stage, estrogen receptor, progesterone receptor status, and marital status, were the independent predictive factors of OM. These variables were selected to generate the nomogram. The calibration curves for 2-, and 5-year OM rate showed excellent agreement between prediction and actual observation. The Brier score and c-index demonstrated the nomogram performed better than the 7th edition TNM staging system for predicting OM possibility. In addition, the nomogram predicted that the magnitude of benefit from adjuvant RT for an individual IBS patient could vary, the certain subgroup of patients (prognostic score: 0-25) would not gain benefit from adjuvant RT, while RT had more pronounced effects in participants with higher prognostic score (prognostic score: ≥25). Conclusions: This nomogram is a reliable prognostic method for predicting OM in IBC patients after surgical resection, which could be used to predict which IBC patients may benefit from adjuvant RT after surgery.
Use of ovarian suppression with endocrine therapy among premenopausal United States women with breast cancer, 2001-2016.
Authors: Mayer Sophie Emma , Lund Jennifer Leigh , Pate Virginia , Reeder-Hayes Katherine Elizabeth
Published: May 2019

e12010

Background: Clinical trials indicate that adding ovarian suppression (OS) to endocrine therapy (ET) in premenopausal women with non-metastatic breast cancer improves disease-free and overall survival. However, injectable OS may add cost, potential side effect burden, and additional clinic visits to adjuvant therapy. It is not known to what extent OS is being used in contemporary community oncology settings. Methods: We identified women age 18-50 with incident breast cancer based on diagnosis codes from 2001-2016 in the commercial IBM MarketScan database. Eligible patients were continuously enrolled for a year prior to cancer diagnosis and filled at least 1 prescription for oral ET (i.e., tamoxifen, toremifene, anastrozole, letrozole, and/or exemestane) in the year after diagnosis. We classified use of OS as any prescription for a gonadotropin-releasing hormone agonist in outpatient pharmacy claims or procedure code for OS implant or injection 1) in the week prior to ET initiation or 2) following ET initiation and for up to 18 months after diagnosis. We estimated the proportion of women that were OS users in each diagnosis year using linear binomial regression, and examined associations between OS use, age at diagnosis, and geographic region. Results: A total of 26,114 women meeting all inclusion criteria were identified from the MarketScan database, of whom 1,452 (5.6%) were OS users. The most common OS drug was leuprolide or leuprorelin (55.2%), followed by goserelin (46.7%), and triptorelin (1.1%). Risk of OS use varied from 3.2% in 2001 to 9.3% in 2016, peaking at 11.4% in 2015. OS use varied by region (χ2 p = 0.0003), with the highest use observed in the Northeast (6.5%) and the lowest in the South (5.0%). Younger patients were significantly more likely to use OS than older patients, with each additional year of age at diagnosis associated with a 0.57 percentage point lower risk (95% confidence interval [CI]: -0.63, -0.51). After controlling for age group (≤40, 41-44, 45-46, 47-48, 49-50) and region, each additional calendar year was associated with 0.25 percentage point greater risk of OS use (95% CI: 0.19, 0.31). Conclusions: OS use with ET appears to be increasing in US breast oncology practice among women under 50.
Modeling longer-term efficacy of neratinib in the extended adjuvant setting for early-stage breast cancer.
Authors: Danese Mark D. , Halperin Marc , Lalla Deepa , Yao Bin , Crown John , Doan Quan V.
Published: May 2019

e12011

Background: Long-term efficacy in the extended adjuvant setting requires a long follow-up. In the ExteNET trial, neratinib was given for a year and invasive disease-free survival (iDFS) assessed at 2 and 5 years. In women with HER2+ hormone receptor positive (HR+) cancer who initiated neratinib, the observed difference in iDFS between neratinib and placebo at 5 years (4.5%) was greater than at 2 years (3.7%). The objective of these analyses was to extrapolate the effect of neratinib on iDFS beyond 5 years in patients with HER2+/HR+ early stage breast cancer who initiated treatment after receiving adjuvant trastuzumab. Methods: We analyzed the 5-year follow-up of the ExteNET trial using flexible spline-based parametric survival models to project iDFS risk at 10 years. Analyses included only HR+ patients. Several model specifications were explored including various combinations of the following variables: treatment as a time varying covariate, nodal status (0, 1-3, ≥4 nodes), and months from last trastuzumab treatment to randomization. The regression models included different combinations of interaction terms, either a proportional hazards or a proportional odds (PO) link function, and either 2 or 6 knots. The model fit was compared using Akaike Information Criterion (AIC). Results: In general, the fit statistics among the 16 models were comparable; however, the model with the lowest AIC included no interaction terms, 2 knots, and the PO link function. The mean iDFS event rate at 10 years was estimated to be 12.2% for neratinib and 18.9% for placebo for a difference of 6.8% (range across 16 models: 6.8%-7.8%). The recurrence rate and the difference between treatment groups were largest in women with ≥4 positive nodes. Conclusions: Based on these analyses, the projected 10-year difference in iDFS between placebo and neratinib patients seems likely to persist. However, because the data was limited to 5 years, we could not include the effect of hormonal therapy cessation. Also, low event rates in the node negative group may require longer follow-up to evaluate. In absence of longer-term data for neratinib, flexible parametric survival modeling of the iDFS suggests that the effect of neratinib therapy may remain stable.
Stratification of oncotype (ODX) Recurrence Score (RS) by Breast Cancer Index (BCI) and its relation to discordance.
Authors: Cascetta Krystal Pauline , Zimmerman Brittney Shulman , Enson Jenna , Ru Meng , Zubizarreta Nicole J. , Jaffer Shabnam , Tiersten Amy
Published: May 2019

e12025

Background: ODX is a gene-expression panel predictive of 10-year risk of distant recurrence and has shown prognostic value in both node-negative (LN-) and node-positive (LN+) breast cancer (BC) patients. BCI predicts 10-year risk of recurrence and also identifies those that may benefit from extended adjuvant endocrine therapy (EET). We stratified ODX RS by BCI to compare its precision in predicting recurrence category and its relation to discordance. Methods: 49 women with HR+, LN- and LN+ BC with available ODX and BCI RS with median follow up of 6 years were included. BCI risk groups were evaluated using predetermined cutoffs. RS were stratified by traditional ODX and TAILORx cutoffs and were considered discordant if there was a 1-step or 2-step difference between ODX risk group (low, intermediate, high) and tumor grade (well, moderately and poorly differentiated). N (%) or median (range) were used to describe patients’ characteristics between BCI groups and compared by chi-square test or Fisher’s exact at the confidence level of 5%. Results: Using traditional RS cutoffs, BCI reclassified 42.3% of patients with low RS as intermediate (IR) or high risk (HR). 69% with intermediate RS were reclassified to low risk (LR) and 12% were upgraded to HR by BCI. 27% of low and intermediate RS had a high benefit from EET. 2-step discordance was 14.3%. Using TAILORx RS cutoffs, BCI reclassified 20% of patients with low RS as IR. None were upgraded to HR. In the intermediate RS group, 58% were reclassified as LR and 14% as HR. 24% of intermediate RS had a high benefit from EET. 2-step discordance was 2%. Conclusions: Patients classified as LR by TAILORx RS cutoffs are less likely to be reclassified as high or intermediate risk by BCI. No significant association was found between discordance among ODX RS and tumor grade and BCI prediction of recurrence or benefit of EET.
BRCA1 tumor expression and clinical outcome in Uruguayan breast cancer patients diagnosed before the age of 40 years.
Authors: Malvasio Silvina , Camejo Natalia , Castillo Cecilia , Artagaveytia Nora , Di Matteo Carina , Caserta Benedicta , Notejane Roberto , Alonso Maria Isabel , Schiavone Andrea , Delgado Lucia Beatriz
Published: May 2019

e12028

Background: BRCA1 is one of the main susceptibility genes for breast cancer (BC). While BRCA1 mutations are rare in sporadic tumors, loss or reduction of gene expression have been reported in approximately 30-50% of sporadic BCs in the general population. From the molecular point of view, there is no clear characterization of these tumors in young women and we have found no studies reporting the rate of under-expression of BRCA1 in women with sporadic BC under 40 years of age. Objective: to assess the tumor expression of BRCA1 using immunohistochemistry (IHC) and its prognostic value in Uruguayan women diagnosed with BC before the age of 40 years. Methods: IHQ was used to analyze the tumor expression of BRCA1 in paraffin-embedded tumor samples of 40 BC patients diagnosed before the age of 40 between 01/01/2006 and 12/31/2012. The optimization and determination of the BRCA1 protein by IHC was centralized. The antibodies used were anti BRCA1 MS110 monoclonal antibodies against the N-terminal end and GLK-2 against the C-terminal end (amino acids 1839-1863). Expression was considered positive when >10% of the cells had nuclear and/or cytoplasmic labeling. Overall survival (OS) and disease free survival (DFS) were calculated; the curves were developed using the Kaplan-Meier method and the difference in survival was evaluated through the log rank test. Results: the average age of the 40 patients included was 36 years; 8 patients (20%) had significant family history of BC or ovarian cancer. The distribution by stage (S) was as follows: SI: 9 patients (22.5%); SII: 20 patients (50%); SIII: 10 patients (25%), and SIV: 1 patient. Regarding the biological profile: 17 patients (42.5%) were HER2- and ER/PR+, 13 (32.5%) were HER2+ and the remaining 10 patients (25%) were classified as triple negative. The 5-year OS and DFS were 73% and 60% respectively. The expression of BRCA1 with GLK-2 was ≤10% in 16 of the 40 patients included (40%). The 5-year OS and DFS for patients with ≤10% expression was 56% vs. 85% for patients with >10% (p = 0.015) and 40% vs. 72% (p = 0.034) respectively. The expression of BRCA1 by MS110 was ≤10% in 11 of the 40 patients included (27.5%). No statistically significant differences were found in the 5-year OS or DFS based on the expression of this marker. Conclusions: Decreased BRCA1 tumor expression as assessed by IHC using GLK-2 was found in 40% of young patients included and was associated with unfavorable prognosis.
Comparison of pegfilgrastim (Peg), plinabulin (Plin), and the combination for chemotherapy (Chemo) induced neutropenia (CIN) prevention: Rationale for the combination.
Authors: Blayney Douglas W. , Ogenstad Stephan , Shi Yuankai , Zhang Qingyuan , Feng Jifeng , Sun Tao , Du Lihua , Huang Lan , Mohanlal Ramon
Published: May 2019

e12030

Background: Peg is used for prevention of CIN. Plin, a novel non-GSF small molecule with anti-cancer activity has equal efficacy against CIN as Peg; Plin does not cause bone pain and mitigates thrombocytopenia and the immune suppressive hematologic profile (Blayney ASCO, ESMO, SITC 2018). Plin has a mechanism of action (MoA) consistent with IL-6 -dependent granulocyte progenitor cell expansion, increased neutrophil demargination and transit from the bone marrow (Suwa, Am J Physiol 2000; Blayney SLB/IEIIS 2018). In single agent (SA) Peg and Plin phase (Ph) 2 data, CIN with Peg occurs in the 1st week (~day (D) 7) post Chemo, and with Plin in the 2nd week (~ D15) post Chemo, presumably due to different MoAs (NCT03102606, NCT03294577). We evaluated whether combining these two agents/MoAs would protect against CIN throughout the entire Chemo cycle (C). Methods: Early stage Breast Cancer Ph 2 patients received high febrile neutropenia (FN) risk TAC (docetaxel, doxorubicin, cyclophosphamide) and either SA standard dose Peg 6 mg (Peg; n=22) or SA Plin (20 mg/m2; n= 15), or Peg 6mg combined with Plin 20 mg/m2 (Peg/Plin; n=16). Peg was given ~24 hrs after TAC, and Plin ~30 min after TAC. Blood draws for ANC were taken daily from predose to Day (D)15, and validated bone pain assessments were done from predose D1 to D8 in C1. Results: On D7 (week 1) of C1, Plin but not Peg maintained mean ANC within normal; P<0.0001 for Plin vs Peg mean ANC. On D15 (week 2 of C1) Peg, but not Plin maintained ANC within normal; P<0.0001 for Peg vs Plin mean ANC. Plin added to Peg maintained mean and median ANC within normal throughout C1. (ANC normal range is 1.5 - 8 x10E9/L.) Frequency of Grade (Gr) 4 and 3/4 CIN was ~35 % lower (P<0.05 for Gr3/4) and median ANC nadir was 2 times higher (1.00 vs 0.46) in Peg/Plin vs Peg in C1. FN occurred in 1 pt each with Peg and Peg/Plin. Incidence of bone pain was 95% vs 6% with Peg vs Peg/Plin (P<0.0001). Conclusions: Adding Plin to standard dose Peg offers superior CIN protection throughout the entire high FN risk Chemo cycle, while almost eradicating bone pain vs Peg alone. Clinical trial information: NCT03294577 .[Table: see text]
The Neat-HER Virtual Registry: A novel registry following HER2+ ESBC patients receiving neratinib in the extended adjuvant setting.
Authors: Tripathy Debu , Vidal Gregory A. , Lalla Deepa , Bryce Richard , Hanson Gillian , Brammer Melissa , Xu Feng , Rugo Hope S.
Published: May 2019

e12035

Background: While data from traditional registries are limited to patients (pts) treated at study sites, virtual registries can enroll a more diverse real-world population. Neat-HER is a US-based, non-interventional pilot virtual registry through PicnicHealth that will enroll 100 pts with HER2+ BC receiving neratinib as extended adjuvant therapy. Methods: Neat-HER will evaluate the feasibility of enrolling pts & answering research questions using this novel methodology. Eligibility includes receipt of neratinib, signed informed consent for medical record retrieval/data abstraction & > 18 years age at study consent. Pts who fail to complete enrollment procedures, are participating in a clinical trial, have metastatic disease, or who lack adequate medical records will be excluded. For each pt discontinuing neratinib within 60 days of starting treatment, an additional pt will be recruited, but all pts will be included in the analysis. Pts are recruited through multiple mechanisms incl. private social media groups, treating clinicians & pts enrolled in the Puma texting program. PicnicHealth will collect & structure medical records from medical practices in the United States for ~7 years prior to enrolment up to 1 year after enrolment. Research questions focus on descriptive pt characteristics & demographics, breast cancer history [(neo)adjuvant treatment/outcomes], use of diarrhea prophylaxis, incidence of diarrhea & duration of neratinib. Results: Enrollment began in 12/2018 with target completion in 4/2019. As of 2/2019, 42 pts have initiated enrolment. Of these, 19 pts completed enrolment & 69,750 data points have been extracted from medical records. Descriptive statistics will be used to characterize the pt cohort. Duration of treatment, receipt & type of prophylaxis, incidence of diarrhea, treatment discontinuation & reasons for discontinuation will be summarized for all pts. Conclusions: A virtual registry allows assessment of medication use & outcomes in a diverse population in a rapid timeframe. Neat-HER will provide comprehensive information on clinical history & treatment patterns in a real-world cohort of pts receiving extended adjuvant neratinib.
Cumulative benefit of multiple agents and drug classes for adjuvant therapy (adj rx) of HER2+ early breast cancer (EBC).
Authors: Holmes Frankie Ann , Brammer Melissa , Dubois Renard , Xu Feng , Yao Bin , Lalla Deepa
Published: May 2019

e12037

Background: Disease-free survival (DFS) in patients with EBC has improved over time. Trials of systemic agents for adj rx of HER2+ BC, including chemotherapies (CT), endocrine, and HER2-targeted agents have reported improved DFS. This review is a high-level overview describing DFS improvements in adj rx HER2+ BC. Methods: Therapeutic agents listed in NCCN guidelines for adj rx HER2+ BC were evaluated for relative and absolute improvements in DFS. Information was derived from US product labels and publications. Hazard ratios, 95% CI, p-values, and DFS differences at 2 and 5 years (if available) are reported. Results: At 2−3 years, adj rx of HER2+ BC with CT and HER2 treatments reported DFS improvements of 4−5% and 0.9−11.3%, respectively. For hormone receptor positive (HR+) BC, unselected by HER2 status, extended adj letrozole had a 1.9% DFS improvement at 2 years; in HR+ HER2+ BC, extended adj neratinib had 4.5% DFS at 2 years. Conclusions: Relative and absolute improvements in DFS in the adj rx BC setting have been largely incremental and cumulative. Absolute improvements in DFS were 0.9−11.3% with CT, HER2 agents, and AIs. In the subset of HR+ / HER2-positive patients, neratinib showed higher DFS improvement compared to non-steroidal AIs. Similar hazard ratios did not always correspond to similar DFS improvements, possibly reflecting differences in baseline risks in the study populations. [Table: see text]
Six cycles of adjuvant anthracycline-taxane-based chemotherapy compared with eight cycles for women with breast cancer.
Authors: Lee Michael , Wilson Sheridan , Porter David James
Published: May 2019

e12045

Background: 3rd generation adjuvant chemotherapy regimens for breast cancer include FEC every three weeks (Q3W) x 3 cycles and Docetaxel (D) Q3W or weekly paclitaxel (P1W) x 9 weeks (FEC-D/P1W) and AC Q3W x 4 followed by P1W x 12 weeks or D x 4 cycles (AC-P1W). These regimens were developed independently and have not been directly compared. Real world effect of weekly paclitaxel schedule is unknown. Methods: Women with stage 1-3 breast cancer who received 3rd generation adjuvant chemotherapy (with 1 year of adjuvant trastuzumab if HER2+) between 2010-2015 inclusive were identified in the New Zealand Breast Cancer Database. Taxane regimens Q3W D and P1W were grouped for analysis. We compared 5 year overall survival (OS) between shorter FEC-D/P1W (total 6 cycles) and longer AC-P1W or Docetaxel Q3W x 4 cycles (total 8 cycles). Patients who received other taxane schedules or non-standard duration of chemotherapy were excluded. Results: 772 women received the FEC-D/P1W regimen and 488 were treated with AC-P1W. The FEC-D/P1W had more grade II/III disease (96.4% v 93.8%), BMI ≥30 (44.7% v 34.5%), HER2 positive (37.8% v 23.6%) and higher chemotherapy completion rate (95.1% v 83.8%). The AC-P1W cohort had higher nodal positive cases (97.1% v 80.6%). Univariate analysis showed no statistical significance for age, BMI, ethnicity, histological subtype and surgery type but tumour grade, stage and hormone status were significant. We constructed a cohort (n = 926) matched for these factors. After median follow up 27 months, 5yr OS for case matched cohort is 87.4% for FEC-D/P1W v 86.4% for AC-D/P1W (p = 0.825) with HR 0.96 (95%CI 0.67-1.38) in favour of FEC-D/P1W. Conclusions: These results suggest one can de-escalate chemotherapy by using a 6 cycle anthracycline/taxane regimen offering an opportunity to reduce the burden of chemotherapy without compromising survival.
The effects of mindfulness meditation and progressive muscle relaxation on fatigue and quality of life in breast cancer patients receiving adjuvant paclitaxel: A three-arm randomized trial.
Authors: Gok Metin Zehra , Izgu Nur , Karadas Canan , Ozdemir Leyla , Demirci Umut
Published: May 2019

e12051

Background: Breast cancer patients often suffer from fatigue during adjuvant paclitaxel regimen which frequently impairs quality of life (QOL). Therefore, this three-arm randomized controlled study aimed to examine the effects of mindfulness-based stress reduction (MBSR) and progressive muscle relaxation (PMR) on fatigue and QOL in breast cancer patients receiving adjuvant paclitaxel. Methods: Participants were randomly assigned to either a MBSR (n = 20), (PMR) (n = 19) or control group (CG) (n = 15). Participants in the intervention groups were instructed on MBSR and PGE, the steps of interventions were recorded a voice recorder and a WhatsApp group was designed by the principal investigator. Participants were asked to listen the recorded audio files during exercises. The intervention groups continued MBSR or PMR 20 min. each day, totally 12 weeks at their home. The CG received only an attention placebo education on breast cancer. Data collection tools included Brief Fatigue Inventory (BFI) and Functional Living Index-Cancer (FLIC). Data were collected at three time points: baseline (T1), week 12 (T2), and week 14 (T3) for follow-up assessment. Kruskal Wallis tests was used for data analysis. Results: BFI scores were significantly lower in the MBSR, PMR groups compared with the CG at T2 and at T3 (p < .01). As for FLIC scores, there were no significant differences between the study groups at T2 and at T3 (p > 0.05). Conclusions: A brief, MBSR and PMR initiated concurrently with adjuvant paclitaxel regimen decreased fatigue severity. Based on the results, MBSR and PMR can be recommended as supportive therapies for breast cancer patients receiving adjuvant paclitaxel.
Using tumor genomic profile testing and comorbidity level to personalize chemotherapy decisions among older patients with early-stage breast cancer.
Authors: Chandler Young , Isaacs Claudine , Jayasekera Jinani , Schechter Clyde B. , Cadham Christopher , Mandelblatt Jeanne S.
Published: May 2019

e12055

Background: Under-representation of women ages 65+ (“older”) in the trials may limit clinical translation of results to this growing population. We used simulation modeling to estimate chemotherapy outcomes by age and comorbidity level among older women with early stage, estrogen-receptor+/HER2- breast cancers with an Oncotype DX score of 26+. Methods: A discrete-time stochastic state-transition model synthesized data from population studies and clinical trials to estimate outcomes over a 25-year horizon for subgroups of women based on age (65-69, 70-74, 75-79, and 80-89) and comorbidity levels (no/low, moderate, and severe). Age-, comorbidity-specific non-cancer survival was derived from a random 5% sample of women enrolled in the Medicare Part A and B program from 1992 to 2005 and included in the SEER areas. Outcomes included life years (LYs), quality-adjusted life years (QALYs), and breast cancer and other-cause mortality with chemoendocrine therapy or endocrine therapy alone. Sensitivity analysis tested the impact on outcomes of varying values of uncertain parameters. Results: Women with life expectancies of ≥ 7 years had net gains of 0.17 to 0.45 LYs (2.0-5.4 months) with chemotherapy; this group was mainly women aged 65-69 and 70-74 with no/low or moderate comorbidity. Women destined to develop distant recurrence gained between 4.2-10.4 months. LYs were reduced by chemotherapy toxicity. The majority of women died of other causes, ranging from 59% to 98% across all age groups and comorbidity levels, but chemotherapy reduced breast cancer mortality by 14.5% and 25.7% among women ages 65-69 and 70-74 with no/low comorbidity, respectively. Results were robust in sensitivity analyses, and chemotherapy improved all outcomes as treatment efficacy increased, assuming no change in toxicity. Conclusions: Older women with early stage, estrogen-receptor+/HER2- breast cancers with Oncotype DX scores of 26+ may benefit from chemotherapy, when both conditions of age <75 and comorbidity at no/low or moderate level can be met. Personalized treatment decisions for older women will ultimately depend on comorbidity-specific lifespan and individual preferences for the balance of benefits and harms of chemotherapy.
Circulating tumor cells in patients with locally advanced breast cancer in evaluation of antitumor treatment efficacy.
Authors: Sagakyants Aleksandr B. , Kit Oleg I. , Samaneva Natalia Yu. , Vladimirova Liubov Yu , Shulgina Oksana G. , Ulianova Elena P. , Novikova Inna A. , Mitashok Irina S , Snezhko Tatiana A.
Published: May 2019

e12064

Background: Circulating tumor cells (CTC) are of great importance in modern cancer research. Biological characteristics of CTC allow using them as tumor markers of high prognostic value. Their quantitative evaluation during treatment can be used to monitor the response to treatment in patients receiving systemic chemotherapy (CT). The purpose of the study was to assess the role of CTC in the prognosis of treatment efficacy in patients with locally advanced Her-2 negative breast cancer. Methods: The study included 42 patients aged 30-65 years with stage IIIA, IIIB, IIIC locally advanced Her-2 negative breast cancer, ECOG-WHO Performance Status from 0 to 2, Karnofsky Performance Status from 100% to 80%. CTC were determined using the CellSearch Veridex System (Johnson & Johnson, USA), taking into account morphological characteristics and expression of epithelial cell adhesion markers EpCAM, CD45 and cytokeratins 8, 18 and 19. Results: CTC were found in 86% (36 of 42 patients) before treatment. CTC were not registered in 6 (14%) patients. 1 CTC was detected in 14% (6 patients); 2-3 CTC – 33% (14 patients); more than 3 CTC – 38% (16 patients). 12% (5) patients showed more than 10 CTC, with the maximum of 64 CTC in 1 patient. After 2 cycles of polychemotherapy, CTC were detected in 50% (21 patients). Other 21 patients did not show presence of CTC. Among CTC-positive patients, 1 CTC was detected in 4 patients (19%); from 2 to 3 CTC – in 9 patients (43%); more than 3 CTC – 8 patients (38%). 2 patients (10%) still showed more than 10 CTC – 28 and 33 CTC in the peripheral blood. After 2 cycles of polychemotherapy, the number of patients with more than 1 CTC decreased from 86% to 50%. Polychemotherapy regimen was changed for patients with increasing amounts of CTC. Conclusions: Determination of the CTC number allows evaluation of the treatment efficacy and is a specific marker for the change of applied polychemotherapy for such cancer type.
Ultrasound-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy with clip and activated charcoal in breast cancer patients: A feasibility study.
Authors: Chae Yee Soo , Lee Soo Jung , Lee In Hee , Jung Jin Hyang , Park Ho Yong , Lee Jeeyeon , Kim Won Hwa , Kim Hye Jung
Published: May 2019

e12067

Background: We report on our experience of ultrasound (US)-guided dual-localization for axillary nodes before and after neoadjuvant chemotherapy (NAC) with clip and activated charcoal to guide axillary surgery in breast cancer patients. Methods: Between November 2017 and May 2018, a dual-localization procedure was performed under US guidance for the most suspicious axillary nodes noted at initial staging (before NAC, with clip) and restaging (after NAC, with activated charcoal) in 28 cytologically proven node-positive breast cancer patients. Patients underwent axillary sampling or dissection, which involved removing not only the sentinel nodes (SNs), but also clipped nodes (CNs) and tattooed nodes (TNs). Success (or failure) rates of biopsies of SNs, CNs, and TNs and inter-nodal concordance rates were determined. Sensitivities for the individual and combined biopsies were calculated. Results: SN biopsy failed in four patients (14%), whereas the CN biopsy failed in one patient (4%). All TNs were identified in the surgical field. Concordance rates were 79% for CNs–TNs, 63% for CNs–SNs, and 58% for TNs–SNs. Sensitivity for SN, CN, and TN biopsy was 73%, 67%, and 67%, respectively. Sensitivity was 80% for any combination of biopsies (SN plus CN, SN plus TN, SN plus CN plus TN). Conclusions: US-guided dual-localization of axillary nodes before and after NAC with clip and activated charcoal was a feasible approach that might facilitate more reliable nodal staging with less-invasive strategies in node-positive breast cancer patients.
Accelerated partial breast irradiation (APBI) using intensity modulated radiation therapy (IMRT) in stage 0-II breast cancer: A preliminary report of 57 cases.
Authors: Mark Rufus J. , Gorman Valerie , McCullough Steven
Published: May 2019

e12068

Background: Randomized trials in Stage 0-II breast cancer have proven that APBI given via HDR implant in 5 days is equivalent to whole breast External Radiation Therapy (XRT) given in 5-6 weeks in regard to breast tumor local recurrence (LR). However, complications have been significant. Recently APBI using non-invasive IMRT given in 5 fractions has been shown in another randomized trial to be equivalent to XRT in 6 weeks, with respect to LR. IMRT was superior in regard to acute effects, late effects, and cosmesis. In the randomized clinical trial of APBI IMRT, the Clinical Target Volume (CTV) was defined by the injection of individual fiducial markers bordering the surgical cavity. At our institution, we have used the Biozorb fiducial system to localize the CTV for IMRT. We sought to confirm the APBI IMRT results with this simpler less labor intensive fiducial placement system. Methods: Between 2017 and 2019, 57 patients have undergone IMRT targeted to a Biozorb defined CTV with the walls of the surgical cavity sewn to the Biozorb device. Eligible patients were older than age 40, had tumor sizes ≤ 3 cm, negative surgical margins, and negative sentinel node dissections. IMRT dose was 30 Gy given in 5 fractions. Dose Constraints were as follows : V-30 Gy < 105%, Ipsilateral Breast V-15 Gy < 50%, Ipsilateral Lung V-10 Gy < 20%, Contralateral Lung V-5 Gy < 10%, Heart V-3 Gy < 20%, Contralateral Breast Dmax < 2 Gy and Skin Dmax < 27 Gy. The Planning Target Volume (PTV) ranged from 27 to 355 cc with a median of 80 cc. PTV = CTV + 1-2 cm. Results: Follow-up ranged from 1-14 months with a median of 7 months. LR has been 0% (0/57). There were no skin reactions. One patient developed pain around the Biozorb site. This resolved within 2 days on a short course of steroids. Cosmetic results as rated by the Surgeon, Radiation Oncologist, and Nurse, were rated excellent in 100% (57/57) of cases. Conclusions: Non-invasive APBI with IMRT targeted to Biozorb has resulted in LR, complications, and cosmetic results which compare favorably to invasive APBI given with HDR implant. At last follow-up, there have been no LR, skin reactions, or complications. Cosmesis has been excellent in 100% of patients.
HIF1A genetic variability and late adverse events of radiotherapy in breast cancer.
Authors: Marinko Tanja , Goricar Katja , Dolzan Vita
Published: May 2019

e12069

Background: Hypoxia-inducible factors (HIFs) are transcription factors that play an important part in the regulation of various cell processes involved in carcinogenesis such as cell proliferation, apoptosis, angiogenesis, and metastasis. Additionally, hypoxia could influence response to radiotherapy and radiation was shown to stabilize HIF-1α and affect release of cytokines. Previous studies have already shown that HIF1A genetic variability may modify cancer susceptibility, but data on its influence on treatment response are scarce. As nicotine induces HIF-1α expression, smoking could also modify treatment response. Our aim was to evaluate the association of common functional HIF1A rs11549465 polymorphism and smoking with late adverse events of radiotherapy in breast cancer patients. Methods: Our pilot retrospective study included 92 HER2-positive early breast cancer patients treated with adjuvant radiotherapy between 2005 and 2011. We isolated DNA from buccal swabs and genotyped all patients for HIF1A rs11549465 using competitive allele-specific PCR. Association of polymorphisms with adverse events and interaction with smoking was evaluated using logistic regression. Results: Median follow-up after radiotherapy was 4.2 (2.6-5.5) years. Overall, 30 (32.6%) patients reported late adverse events according to LENT-SOMA criteria, and 11 (12.0%) experienced skin toxicity according to CTCAE v.4.0 (Common Terminology Criteria for Adverse Events). Only 15 (16.3%) of patients were smokers. Minor allele frequency of HIF1A rs11549465 was 0.07. The studied polymorphism was not associated with late adverse events (OR = 0.75, 95% CI = 0.18-3.06, P = 0.688) or late skin toxicity (OR = 0.71, 95% CI = 0.08-6.15, P = 0.756) in our cohort of patients. We also observed no interaction between smoking, HIF1A genetic variability and late adverse events of radiotherapy. Conclusions: HIF1A rs11549465 was not associated with late adverse events of radiotherapy even if smoking was taken into account in our cohort of breast cancer patients.
Automated artificial intelligence quantification of fibroglandular tissue on breast MRI.
Authors: Takhtawala Ruquaiyah , Tapia Negrete Nataly , Shaver Madeleine , Kart Turkay , Zhang Yang , Park Vivian Youngjean , Kim Min Jung , Su Min-Ying , Chow Daniel S. , Chang Peter
Published: May 2019

e12071

Background: The objective of this study is to examine if a convolutional neural network can be utilized to automate breast fibroglandular tissue segmentation, a risk factor for breast cancer, on MRIs. Methods: This institutional review board approved study assessed retrospectively acquired MRI T1 pre-contrast image data for 238 patients. Ground truth parameters were derived through manual segmentation. A hybrid 3D/2D U-Net architecture was developed for fibroglandular tissue segmentation. The network was trained with T1 pre-contrast MRI data and their corresponding ground-truth labels. The analysis was started with image pre-processing. Each MRI volume was re-sampled and normalized using z-scores. Convolution operations reduced 3D volumes into a 2D slice in the contracting arm of the U-Net architecture. Results: A 5-fold cross validation was performed and the Dice similarity coefficient was used to assess the accuracy of fibroglandular tissue segmentation. Cross-validation results showed that the automated hybrid CNN approach resulted in a Dice similarity coefficient of 0.848 and a Pearson correlation of 0.961 in comparison to the ground-truth for fibroglandular breast tissue segmentation, which demonstrates high accuracy. Conclusions: The results demonstrate significant application of deep learning in accurately automating segmentation of breast fibroglandular tissue.
Influence of radiation therapy on the outcome of T1-2N0M0 triple-negative breast cancer: A SEER population-based retrospective analysis.
Authors: Guan Xiaoxiang , Li Huan , Chen Yajuan , Wang Xin , Tang Lin , Wang Yucai , Shu Yongqian
Published: May 2019

e12073

Background: For T1-2N0M0 breast cancer after surgery and axillary staging, the current NCCN guideline recommends radiation therapy (RT) after lumpectomy but not total mastectomy unless there is a positive or less than 1 mm negative margin. This recommendation is regardless of hormonal status. Triple-negative breast cancer is a generally considered more aggressive compared with hormone positive breast cancer. We sought to investigate whether there is a survival benefit of RT in T1-2N0M0 TNBC. Methods: A Population-based retrospective analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) database. Patients included in the analysis were divided into three groups according to surgery modality and RT: breast conservation therapy (BCT, i.e., lumpectomy + RT), mastectomy alone, and mastectomy + RT. The survival endpoints were breast cancer-specific survival (BCSS) and overall survival (OS), and survival analysis was performed using the Kaplan-Meier method. Results: A total of 22473 female with T1-2N0M0 TNBC diagnosed between 2010 and 2015 were included, with 13395 (60%) T1 and 9078 (40%) T2 cases. Surgery, RT and chemotherapy was done in 21674 (96%), 9633 (43%) and 14651 (65%) patients, respectively. Patients who underwent RT were older ( > 50 years, 78% vs 72%, P< 0.001), had fewer T2 (35% vs 44%, P< 0.001) tumor, and had more chemotherapy utilization (72% vs 60%, P< 0.001). 8807 patients had BCT; 8329 had mastectomy alone and 635 had mastectomy + RT. The 5-year BCSS rate was 94.3% for BCT, 93.3% for mastectomy alone ( P= 0.009 vs BCT), and 83.7% for mastectomy + RT ( P< 0.001 vs BCT and P< 0.001 vs mastectomy alone), respectively. The 5-year OS rate was 88.6% for BCT, 83.0 % for mastectomy alone ( P< 0.001 vs BCT), and 79.6% for mastectomy + RT ( P< 0.001 vs BCT and P= 0.190 vs mastectomy alone), respectively. Conclusions: In patients with T1-2N0M0 TNBC, BCT was associated with superior BCSS and OS compared to mastectomy with or without RT. After mastectomy, there was no evidence of survival benefit of RT, with worse BCSS and similar OS.