bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel biosignature identifies DCIS patients with a poor biologic subtype with an unacceptably high rate of local recurrence after breast conserving surgery and radiotherapy.
Authors: Vicini Frank , Shah Chirag , Whitworth Pat W. , Shivers Steven C , Warnberg Fredrik , Mann Bruce , Bremer Troy 
Published: June 2021

513 Background: There is an unmet need to identify women diagnosed with DCIS who have a low recurrence risk and could omit radiotherapy (RT) after breast conserving surgery (BCS), or an elevated recurrence risk after treatment with BCS plus RT. DCISionRT and its response subtype (Rst) biosignature were evaluated in a contemporary cohort treated with BCS with or without RT to identify these risk groups. Methods: Pathology, clinical data, and FFPE tissue samples were evaluable for 485 women diagnosed with DCIS at centers in Sweden (1996-2004), the USA (1999-2008), and Australia (2006-2011). Patients were treated with BCS (negative margins) with or without whole breast RT. Ipsilateral breast tumor recurrence (IBTR) included DCIS or invasive breast cancer (IBC) that was local, regional, or metastatic. The patients were classified into Low and Elevated risk groups to assess IBTR and IBC rates. Patients in the Elevated risk group were categorized by two subtypes: a good response subtype (good Rst) or a poor response subtype (poor Rst) after BCS plus RT. Biosignatures were calculated using biomarkers (p16/INK4A, Ki-67, COX-2, PgR, HER2, FOXA1, SIAH2) assayed using IHC on FFPE tissue. Hazard ratios and 10-year risks were calculated using Cox proportional hazards (CPH) and Kaplan-Meier analyses. Results: In the DCISionRT Elevated risk group, RT was associated with significantly reduced recurrence rates, but only for those patients with a good Rst (Table, IBTR HR=0.18, p<0.001, IBC HR=0.15, p=0.003, n=241). For Elevated risk group patients with a poor Rst, no benefit to RT was noted (Table). Additionally, irrespective of RT, patients with a poor Rst had 10-year IBTR/IBC rates of 25%/16%, which were much higher than good Rst rates of 6.6%/4.5% (IBE HR=3.6, p=0.02, IBC HR=4.4, p=0.04, n=190). For patients in the Low risk group, there was no significant difference in 10-year IBTR/IBC rates with and without RT (Table, IBTR p=0.4, IBC p=0.9, n=177). The distribution of clinicopathologic risk factors (age <50 years, grade 3, size >2.5 cm) did not identify poor vs. good response subtypes, and multivariable analysis (n=485) indicated these traditional clinicopathologic factors and endocrine therapy were not significantly associated with IBTR (p≥0.22) or IBC (p≥0.34). Conclusions: Biosignatures identified a Low risk patient group with low 10-year recurrence rates with or without RT who may be candidates for omitting adjuvant RT. Biosignatures also identified an Elevated risk group receiving BCS plus RT with a poor response subtype that had unacceptably high recurrence rates, warranting potential intensified or alternate therapy.[Table: see text]
Long-term results of simplified lymphatic microsurgical preventing healing approach (SLYMPHA) for the prevention of breast cancer-related clinical lymphedema after axillary lymph node dissection.
Authors: Ozmen Tolga , Layton Christina , Friedman-Eldar Orli , Melnikau Siarhei , Kesmodel Susan , Avisar Eli 
Published: June 2021

514 Background: Lymphedema (LE) is a serious complication of axillary lymph node dissection (ALND) with an incidence rate of 16%. SLYMPHA is a safe and relatively simple method, which decreases incidence of LE dramatically. Our initial study showed an 88% decrease in clinical LE rate after a median follow up of 15 months. The aim of this study was to confirm these results after a longer follow up period. Methods: All patients, undergoing ALND between January 2014 and November 2020 were included in the study. During follow-up visits, tape-measuring limb circumference method was used to detect clinical LE. The incidence of clinical LE was compared between patients with and without SLYMPHA. Univariate and multivariate analysis were used to assess the role of other factors in the appearance of clinical LE. Results: 580 patients were included in the study. 35% of cohort underwent SLYMPHA. Mean follow-up time was 44 ±31.9 months. Patients, who underwent SLYMPHA, had a significantly lower LE rate (10% vs 26%; p=0.002; OR 0.4 [0.31-0.77]). Diabetes and removing ³22 lymph nodes also correlated with increased LE however this effect disappeared on multivariate analysis. Conclusions: SLYMPHA is a safe and relatively simple method, which continued its efficacy after 4-years follow up. It should be considered as an adjunct procedure to ALND for all patients during initial surgery.[Table: see text]
Efficacy of epirubicin plus cyclophosphamide followed by taxanes versus carboplatin plus taxanes as adjuvant chemotherapy in triple-negative breast cancer: 8.1 years median follow-up on a randomized clinical trial.
Authors: Zheng Fangchao , Du Feng , Wang Yongsheng , Wang Xue , Wang Jiayu , Yue Jian , Ma Fei , Fan Ying , Xu Binghe , Yuan Peng 
Published: June 2021

529 Background: Four cycles of adjuvant taxanes (paclitaxel or docetaxel) after four cycles of adjuvant doxorubicin plus cyclophosphamide (ECT) are considered a standard adjuvant treatment and improves survival outcomes of triple negative breast cancer (TNBC). The purpose of this analysis was to further assess whether adjuvant carboplatin plus taxanes (TP) was non-inferior to or superior to standard ECT chemotherapy in prolonging the survival time. Methods: This randomized, open-label, multicenter clinical trial conducted at three hospital in China from June, 2009 and October, 2015. Eligible early triple-negative breast cancer (TNBC) patients were randomized (1:1) to receive ECT (four cycles of epirubicin 90 mg/m2 + cyclophosphamide 600 mg/m2 followed by four cycles of docetaxel 75 mg/m2 or paclitaxel 175 mg/m2 every 3 weeks, ECT arm, n = 154) or receive TP (six cycles of docetaxel 75 mg/m2 or paclitaxel 175 mg/m2 + carboplatin AUC 5 every 3 weeks; TP arm, n = 154), which was then followed by surgery. Results: Three hundred and eight patients were recruited in this trial and final date of follow-up was January 20, 2021. Baseline characteristics were balanced between ECT arm and TP arm. Median follow-up was 97.6 months. Median disease free survival (DFS) was not reached; 8-year DFS rate was 78.35% with ECT arm and 81.73% with TP arm (hazard ratio [HR] = 0.84; 95% confidence interval [CI] = 0.50 - 1.40; P = 0.496). Median overall survival (OS) was also not reached; 8-year OS rate was 87.15% with ECT arm and 89.14% with TP arm (HR = 0.87; 95% CI = 0.44 - 1.70; P = 0.676). For TNBC patients with DFS > 4 year, TP arm had a longer DFS than ECT ( P = 0.01), and had a tendency with better OS ( P = 0.4). In this subgroup analysis of SPARC > 50%, TP arm had a longer DFS than ECT ( P < 0.05), and also had a tendency with better OS ( P = 0.06). In subgroup analysis of PD-1 (-) and intravascular invasion (+), TP arm had a better DFS ( P = 0.02) and OS ( P = 0.03) than ECT arm. DFS or OS had no significant differences in ECT and TP arm with BRCA mutation or BRCA wild ( all P values > 0.05). Conclusions: TP chemotherapy showed significant non-inferiority for PFS and OS versus ECT in the first-line adjuvant treatment of early TNBC. For some particular subgroup of TNBC, TP may be a more effective chemotherapy than ECT. TP may be considered an effective alternative to early TNBC. Clinical trial information: NCT01150513.
Use of a novel convolutional neural network-based mammographic evaluation to assess response to adjuvant endocrine therapy in women with early-stage breast cancer.
Authors: McGuinness Julia Elizabeth , Ro Vicky , Mutasa Simukayi , Ha Richard , Crew Katherine D. 
Published: June 2021

530 Background: The standard of care for early-stage hormone receptor (HR)-positive breast cancer (BC) is 5-10 years of adjuvant endocrine therapy (ET), which leads to a 50-60% relative risk reduction in BC recurrence. However, 10-40% of patients may relapse up to 20 years (y) after diagnosis, and there is a need for biomarkers of response to ET. We developed a novel, fully-automated convolutional neural network (CNN)-based mammographic evaluation that accurately predicts BC risk, which is being evaluated as a pharmacodynamic response biomarker to adjuvant ET. Methods: We conducted a retrospective cohort study among women with HR-positive stage I-III unilateral BC diagnosed at Columbia University Irving Medical Center from 2007-2017, who received adjuvant ET and had at least 2 mammograms of the contralateral breast (baseline and annual follow-up). Demographics, clinical characteristics, BC treatments, and relapse status were extracted from the electronic health record and New York-Presbyterian Hospital Tumor Registry. We performed CNN analysis of mammograms at baseline (start of ET) and annual follow-up. Our primary endpoint was change in CNN risk score, expressed as a continuous variable (range, 0-1). We used two-sample t-tests to assess for differences in mean CNN scores between patients who relapsed or remained in remission. We evaluated if CNN score at baseline and change from baseline were associated with relapse using logistic regression, with adjustment for known prognostic factors. Results: Among 870 evaluable women, mean age at diagnosis was 59.5y (standard deviation [SD], 12.4); 60.3% had stage I tumors, 72.6% underwent lumpectomy, and 45.8% received chemotherapy. With a median follow-up of 4.9y, there were 68 (7.9%) breast cancer relapses (36 distant, 26 local, 6 new primary). Median number of evaluable mammograms per patient was 5 (range, 2-13). Mean baseline CNN risk scores were significantly higher among women who relapsed compared to those in remission (0.258 vs 0.237, p = 0.022), which remained significant after adjustment for known prognostic factors. There was a significant difference in mean absolute change in CNN risk score from baseline to 1y follow-up between those who relapsed vs. remained in remission (0.001 vs. -0.022, p = 0.027), but this was no longer significant in multivariable analysis. Conclusions: We demonstrated that higher baseline CNN risk score was an independent predictor of BC relapse. A greater decrease in mean CNN risk scores at 1-year follow-up after initiating adjuvant ET was seen among BC patients who remained in remission compared to those who relapsed. Therefore, baseline CNN risk scores may identify patients at high-risk for breast cancer recurrence to target for more intensive adjuvant treatment. Early changes in CNN risk scores may be used to predict response to long-term ET in the adjuvant setting.
Impact of endocrine therapy on overall survival in ER negative/PR positive locoregional breast cancer: An analysis of the National Cancer Database.
Authors: Kollu Vidya , Osterloth Kohei , Borgert Andrew J. , Frankki Susan M. , Parsons Benjamin Marshall 
Published: June 2021

545 Background: Breast cancer expressing PR, but not ER (ER-/PR+) are uncommon, comprising 2–8% of breast cancers, with less known about their characteristics and responsiveness to therapy. The role of adjuvant endocrine therapy (ET) in ER-/PR+ locoregional breast cancer is unclear as these patients have been largely excluded from prospective clinical trials. Despite a lack of data patients are often treated with adjuvant ET due to perceived possible benefit. We used the National Cancer Data Base (NCDB) to assess role of adjuvant ET in ER-/PR + breast cancer. Methods: Using the NCDB, we included adults ≥ 18 and ≤ 70 years old in order to minimize the non-cancer related deaths. We selected only female patients with stage I, II, and III. Patients have received definitive surgery (lumpectomy with radiation or mastectomy) with negative margins. Systemic therapy (ST) was defined as receipt of chemotherapy and/or immunotherapy. We excluded those who had unknown ST status, unknown ET status, unknown HER 2 status, who did not receive definitive surgery and those whose survival time was missing. Patients were stratified into four groups based on HER2 status and receipt of ET. Both Multivariable Cox proportional hazards regression modeling was utilized to determine predictors of overall survival (OS). A propensity score matched cohort was developed based on relevant demographic and clinical factors. The primary endpoint assessed was OS. All analyses were performed using SAS 9.4. Results: We identified 5344 patients (74% were Caucasian, 20% were African American and 6% were others) with ER-/PR+(74% were HER2 - and 26% were HER2 +) locoregional breast cancer (51% were Stage I, 38 % were stage II and 11% were stage III). Grade 1 cancer was seen in 2%, grade 2 in 18%, and majority being grade 3 in 80%. Of which 3093 (58%) patients received ET and 4462 (83%) received ST. Majority of patients were in age group 50-70 comprising of 69% patients, 8 % in age 18—39, 23% in age 40-49 with Charlson-Deyo Score of 0 in 83%, 1 in13%, 2-3 in 4%. In a propensity matched cohort (N=3980), ET was not significantly associated with OS among HER2 negative (HER2-) patients (HR=1.05, 95% CI 0.86-1.28, p=0.63). In HER2+ patient ET was associated with significantly improved OS (HR=0.65, 95% CI 0.42-0.99, p=.047). Conclusions: Receiving ET was not associated with improved OS in locoregional ER-/PR+/HER2- breast cancer based on our study using a propensity matched cohort in the NCDB. However, was frequently administered. Interestingly, improved OS was seen in locoregional ER-/PR+/HER2+ breast cancer with adjuvant ET.
Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1.
Authors: Blayney Douglas W. , Shi Yuankai , Bondarenko Igor , Ogenstad Stephan , Zhang Qingyuan , Du Lihua , Huang Lan , Mohanlal Ramon 
Published: June 2021

547 Background: Peg is the current standard of care (SoC) for the prevention of CIN, with a low absolute neutrophil (N) count (ANC) week 1 after chemotherapy (chemo) with normalization in week 2. Breakthrough designation agent from FDA, Plin, a novel, non-G-CSF agent for the prevention of CIN, produces a normal ANC in week 1 of cycle (C) 1 by potentially protecting progenitor cells in bone marrow from chemo assault, and also has anticancer activity (Blayney, St Gallen 2019; ASCO 2019). Here we report data from a pre-specified interim analysis from PROTECTIVE-1 (Study 105; NCT03102606). Methods: Breast cancer (BC), lung (NSCLC) and prostate cancer (HRPC) pts with at least 1 risk factor as per NCCN, received docetaxel (Doc) 75 mg/m2 with either Peg 6mg (n=53) or Plin 40 mg (n=52) over 4 cycles, and had ANC blood draws on Day (D) 1, 2,6,7,8,9,10,15 in C1 (Covance Central Laboratory). Plin was given on D1, as a 30 min IV infusion, 30 min after Doc, and Peg, 24 hrs after Doc. Primary objective was to demonstrate non-inferiority (NI) of SA Plin vs SA Peg for duration of severe neutropenia (DSN) in C1. NI of Plin vs Peg would be declared if the upper limit of 95% confidence interval for the mean DSN difference between Plin and Peg would be <0.65 day. Other endpoints included C1 platelet count, C1 bone pain scores (validated questionnaire), C1-4 clinical sequelae of CIN through [febrile neutropenia (FN), infection, antibiotic and hospitalization rate, and Doc discontinuation (Discont) and delays], and safety (AEs, hematology and chemistry, vital signs) Results: Predefined DSN NI criterion between SA Plin and SA Peg was met. C1 Grade 4 toxicity was not different between Plin and Peg (p=NS). Clinical sequelae of CIN were comparable or slightly better for Plin vs Peg (see Table). Plin caused less bone pain (p=0.01) and less thrombocytopenia (p<0.0001 on D15) vs Peg. AE frequency and overall safety was comparable for SA Plin and SA Peg. Conclusions: SA Plin has efficacy for Doc CIN prevention non-inferior compared to SoC Peg, and accordingly has comparable (or numerically better) profile for clinical sequelae of CIN. Plin has an advantage for bone pain, platelet counts, convenience of use (same day vs next day dosing) over SoC Peg and has anticancer activity. Clinical trial information: NCT03102606. [Table: see text]
Use of a high-sensitivity anti-Mullerian hormone (AMH) assay to determine ovarian function after chemotherapy for early breast cancer.
Authors: Clatot Florian , Thomas Kelsey , Lambertini Matteo , Olympios Nathalie , Duhamel Orianne , Perdrix Anne , Anderson Richard 
Published: June 2021

552 Background: It is now well established that AMH can indicate the extent of chemotherapy-induced damage on the ovarian reserve. Very low AMH levels in women after chemotherapy for early breast cancer (eBC) may indicate treatment-induced premature ovarian failure (POI), but the evidence to implement its routine clinical use remains limited. Methods: AMH was measured (Roche cobas autoanalyser) in 197 women aged 40-45 years at diagnosis treated with anthracycline/cyclophosphamide/taxane based chemotherapy for eBC, with no previous endocrine therapy and no subsequent aromatase inhibitor exposure or ovarian suppression. 76% were ER positive and received tamoxifen. The primary objective was to assess the relationships between AMH levels at 6 months after chemotherapy (AMH6) with subsequent ovarian function at 30 months. This included accuracy of prediction of loss of ovarian function at 30 months (E30) after chemotherapy by AMH levels at 6 months (AMH6) and the value of other endocrine/clinical factors pretreatment and at 6 months. Multivariate analysis was performed with data were split into 70% training and 30% testing sets with results reported for model performance on the test set. Results: AMH fell from a median of 0.62 (IQR 0.21-1.31) ng/ml pretreatment to become undetectable ( < 0.01ng/ml) in 137 (70%) of women at 6 months. AMH showed very little recovery, being undetectable in 115 women at 18 months and 119 at 30 months. In those with detectable AMH at 30 months, it remained very low, median 0.07ng/ml, max 0.82ng/ml but nevertheless it reflected ovarian function. Thus median estradiol at 30 months (E30) was 50 pmol/l (IQR 34-68) in women with undetectable AMH at that time, vs 313 pmol/l (IQR 102-1052) in the 80 women with detectable AMH. AMH at 6 months was predictive of ovarian function at 30 months, as E30 was 56 pmol/l (IQR 40-104) in women with undetectable AMH6 vs 258pmol/l (IQR 69-780; p < 0.0001) in women with detectable AMH6, and the positive predictive value (PPV) of AMH being undetectable at 6 months and remaining so at 30 months was 77%. Random forest analysis identified BMI as a non-endocrine predictive factor of E30. Using a stringent cutoff of ≤50pmol/l (13.6 pg/ml) and adding 1:9 weighting to improve PPV gave a test validated PPV of 79.0% while maintaining AUC at 83.7% for prediction of E30. Other classifiers performed less well than random forests. Conclusions: Measurement of AMH at 6 months after chemotherapy has predictive value for later ovarian function, and combining this with other endocrine and baseline data improves discriminative ability. This approach indicates the potential role of multivariate analysis based on AMH measured shortly after chemotherapy to helping optimise subsequent endocrine therapy.
Discovery and validation of novel methylated DNA markers of cervical cancer.
Authors: Bakkum-Gamez Jamie Nadine , Graham Rondell P. , Broderick Brendan T. , Slettedahl Seth , Mahoney Douglas W. , Lemens Maureen , Cao Xiaoming , Foote Patrick H. , Burger Kelli , Berger Calise K. , O'Connell Maria , Doering Karen A. , Schoolmeester J. Kenneth , Kerr Sarah , Taylor William R. , Sherman Mark E. , Kisiel John B. 
Published: June 2021

5526 Background: HR-HPV DNA testing, with or without cervical cytology, provides excellent sensitivity for detection of cervical cancer (CC) and its precursors; negative test results indicate that risk of disease is extremely low and enable women to undergo reduced screening with safety. However, management of women who screen positive remains challenging as many will prove to have self-limited HR-HPV infections. DNA methylation is an early event in carcinogenesis that could enhance CC screening specificity. Methods: For discovery, DNA from 70 FFPE CC (36 squamous, 34 adenocarcinoma) tissues that were reviewed microscopically, 18 fresh frozen benign cervicovaginal (BCV) tissues collected at the time of benign hysterectomy, and 18 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with CC. Candidate MDM selection was based on area under the receiver operating characteristic curve (AUC) discrimination, methylation fold change, and low background methylation among benign controls. Candidate MDMs were re-tested using methylation-specific PCR (MSP) to confirm performance. Blinded biological validation was performed using MSP on DNA extracted from independent FFPE CC (38 squamous, 43 adenocarcinoma) and BCV (40) tissues. The performance of CC MDMs was also tested in DNA extracted from cervical dysplasia (36 adenocarcinoma in situ (AIS), 32 cervical intraepithelial neoplasia (CIN) 2/3, 11 CIN 1) FFPE tissues. Results: From RRBS discovery and technical validation via MSP, 30 candidate MDMs showed marked methylation fold changes (10 to >1000) across both CC histologies compared to BCV tissue from cancer-free women. Each of the 30 MDMs highly discriminated CC from BCV tissue with 9 MDMs having an AUC >0.90 (Table). CC MDMs also highly discriminated AIS from BCV but did not perform well in CIN 2/3 and CIN 1 (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation have yielded outstanding candidate MDMs for CC that highly discriminate CC from BCV, notably with high specificity. Performance in cervical dysplasias varied with higher positivity rates in AIS than in CIN 2/3 and CIN 1. Translation to testing these novel MDMs in lower genital tract biospecimens and the addition of HR-HPV to the CC panel are warranted.[Table: see text]