bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for HER2+ locally recurrent or metastatic breast cancer (MBC): Results from a phase 2, single-arm, multicenter study.
Authors: O'Shaughnessy Joyce , Huggins-Puhalla Shannon Leigh , Wilks Sharon , Brufsky Adam , Schwartzberg Lee Steven , Berrak Erhan , Song James X. , Cox David , Vahdat Linda T. 
Published: February 2017

139 Background: Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for women with MBC who previously received ≥ 2 chemotherapy regimens in the metastatic setting. Primary data from a phase 2 trial on first-line combination eribulin + trastuzumab (TRAS) in HER2+ patients (pts) showed a 71% objective response rate (ORR) and tolerability consistent with the known profile of these agents. Here we present prespecified endpoint data for this study by prior TRAS use. Methods: Pts with HER2+ MBC who had not received prior chemotherapy for MBC received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle and initial TRAS (8 mg/kg IV/day 1), followed by 6 mg/kg/day 1 of each subsequent cycle. Response, progression-free survival (PFS), and tolerability were assessed in patients who had and had not received prior TRAS treatment. Results: The 52 pts (median age, 59.5 years) received combination eribulin + TRAS, for a median treatment duration of ~30 weeks; 40% (n=21) were previously treated with TRAS in the neo-adjuvant/adjuvant setting. There was median of 23 months since completion of adjuvant treatment prior to retreatment with eribulin + TRAS for first-line MBC.Efficacy, assessed by ORR, clinical benefit rate (CBR), PFS, and duration of response (DOR), was largely consistent in pts who received prior TRAS relative to pts who had not received prior TRAS (see table). Overall, grade (G) 3-5 adverse events (AEs), treatment-related AEs (TRAEs), and discontinuations (d/c) were similar between groups (Table). Conclusions: In this phase 2 single-arm trial in pts with HER2+ MBC, eribulin + TRAS demonstrated activity and was well tolerated as first-line treatment, irrespective of prior (neo) adjuvant TRAS treatment. Clinical trial information: NCT01269346. [Table: see text]
Overall survival (OS) in metastatic breast cancer (MBC): Are we using the right endpoint in the right way?
Authors: Raphael Jacques , Verma Sunil 
Published: February 2017

142 Background: OS has been historically considered the most important clinical endpoint in MBC trials; however survival could be influenced by treatment after progression in an era of effective subsequent-line agents. Methods: We conducted a search strategy using PubMed for randomized phase 3 trials published in the last 2 decades (1994-2014) evaluating survival outcome in MBC. We investigated the frequency of trials reporting post progression outcome and response/resistance to treatment beyond progression. Results: 110 trials met our eligibility criteria: 69 (63%) evaluated chemotherapy regimens (group A), 27 (25%) evaluated targeted therapy (group B) and 14 (13%) focused on endocrine treatment (group C). The majority of the trials had OS as a primary or secondary endpoint (97% (66/69), 100% (27/27) and 86% (12/14) of the trials in group A, B and C respectively). An OS benefit was demonstrated in approximately 22% of the trials in each group. Post progression survival (PPS) and its effect on OS was reported and discussed in only 1% (1/69), 4% (1/27) and 7% (1/14) of the trials for group A, B and C respectively. Less than 10% of the trials in group A and B reported response data and duration of response after progression on trial therapy. In addition, post progression treatment resistance was only reported in group A in 3% (2/69) of the trials. Furthermore, the number of lines of treatment used post progression was reported in only 14% (10/69), 11% (3/27) and 14% (2/14) of the trials in group A, B and C respectively. Conclusions: A clear paucity of post progression treatment information is noted in the majority of the phase 3 trials for MBC. We do know that OS is directly affected by treatments used after progression. In order to assess the true clinical benefit of a new drug and a complete evaluation of overall survival outcome, a detailed collection of post progression treatment information is required and should be mandated in MBC clinical studies.
Obesity and guideline-concordant systemic therapy for locoregional breast cancer.
Authors: Moore Hollis , Trentham-Dietz Amy , Greenberg Caprice Christian , Vanness David J. , Hampton John M , Wu Xiao-cheng , Anderson Roger T. , Lipscomb Joseph , Kimmick Gretchen Genevieve , Cress Rosemary Donaldson , Fleming Steven , Wilson J. Frank 
Published: February 2017

145 Background: Obese breast cancer patients tend to have higher mortality than non-obese patients. Hypothesizing that differences in receipt of adequate treatment may contribute to this mortality differential, we examined whether breast cancer patients with higher body mass index (BMI) received systemic adjuvant treatment consistent with National Comprehensive Cancer Network guidelines. Methods: Female adult stage I-III breast cancer cases diagnosed in 2004 were identified from population-based cancer registries in 7 states and supplemented with abstracted medical records. Differences in receipt of concordant treatment according to BMI were investigated using logistic regression models adjusted for age and other covariates. Results: Among all women, 57% (2,174 of 3,828) received overall guideline-concordant (GC) adjuvant systemic treatment, meaning treatment adherent in each of 3 defined domains: chemotherapy, chemotherapy regimen, and hormonal therapy. Within the domains, 82% of women received GC chemotherapy, and 93% of those received a GC regimen, and 80% received GC hormonal therapy. Women with higher BMI had greater odds of receiving GC systemic therapy (odds ratio for each 5 kg/m2 increase in BMI 1.07, 95% CI 1.01 to 1.14; p value for trend = 0.04). No significant differences in guideline treatment according to BMI were found in the individual therapy domains (adjuvant chemotherapy, p = 0.18; chemotherapy regimen, p = 0.26), although a borderline significant, nonlinear pattern was seen for hormonal therapy, in which the highest odds of GC treatment were found in the lowest and highest BMI ranges (p = 0.07 from χ2 test). Conclusions: Contrary to our hypothesis, odds of guideline concordant systemic therapy increased with higher BMI, and no significant differences were found within any specific treatment domain. Further research describing how multiple factors including treatment patterns influence outcomes for obese breast cancer patients may identify areas where changes in practice can reduce disease burden and mortality. Our research also suggests further investigation into patterns of care for underweight patients.
Peripheral neuropathy (PN) in patients (pts) with metastatic breast cancer treated with eribulin: Resolution and association with efficacy.
Authors: Kaufman Peter , Olivo Martin , He Yi , McCutcheon Susan , Vahdat Linda 
Published: February 2017

147 Background: PN is a known adverse effect of various antimicrotubule agents, including eribulin. We report here the incidence and resolution of PN in breast cancer pts treated with eribulin in completed phase 2 and 3 studies, and the efficacy of eribulin in pts with PN in the phase 3 EMBRACE and 301 studies. Methods: In EMBRACE, women had received 2-5 lines of chemotherapy for advanced disease. In this ≥ 3rd-line setting, pts randomized to eribulin mesylate received it at 1.4 mg/m2 iv, days 1 and 8 every 21 days. The dosing schedule was the same in study 301, which involved pts who had received 0-2 prior chemotherapies for advanced disease. Overall survival (OS) and progression-free survival (PFS) were analyzed by stratified log-rank test. Data from EMBRACE and 301 were pooled with data from 2 phase 2 studies to assess time to improvement (a decrease of ≥ 1 grade) and resolution (decrease in grade to 0, 1 or baseline) of grade 3 or 4 PN. Results: In the pooled safety analysis, 7.7% (116/1503) of pts treated with eribulin had grade 3 or 4 PN; 63.8% of these experienced improvement in PN and 50% had resolution. Median time to improvement was 2.1 weeks and to resolution was 7.7 weeks. Characteristics were similar in pts with or without PN in EMBRACE and 301. Those with PN had longer exposure to eribulin vs pts without PN (median exposure [months], study 301: 4.9 vs 3.2; EMBRACE: 4.8 vs 2.9). OS and PFS were significantly longer in pts with PN (Table). Conclusions: Pts who had a favourable therapeutic response to eribulin, received a longer course of treatment and thus had a greater risk of PN. Severity of PN improved in most pts within a short period. Regarding PN, the risk–benefit ratio for eribulin supports treatment. Clinical trial information: NCT00337103, NCT00388726. [Table: see text]
A phase 1 study of dinaciclib (SCH 727965) in combination with epirubicinin patients with metastatic triple-negative breast cancer.
Authors: Mitri Zahi , Karakas Kansu , Ibrahim Nuhad K. , Alvarez Ricardo H. , Murray James L. , Briones Brian , Simmons Holly , Keyomarsi Khandan , Moulder Stacy L. 
Published: February 2017

163 Background: Low molecular weight cyclin E (LMW-E) isoforms are overexpressed in a majority (~70%) of triple-negative breast cancers (TNBC). LMW-E isoforms have a role in tumorigenesis, likely mediated through binding and activation of CDK2. The combination of CDK1/CDK2 inhibitors, such as dinaciclib, with an anthracycline was found to be synergistic in decreasing viability of TNBC cell lines. Based on this data, we conducted a phase 1 study aimed to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. Methods: Cohorts of at least 2 patients were treated with escalating doses of dinaciclib (20-50 mg/m2) given on day 1 followed by standard dose of epirubicin (75 mg/m2) given on day 2 of a 21 day cycle. All patients received pegfilagrastim 24-48 hours after chemotherapy. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30%. Results: Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. Patient characteristics are included in the Table. One patient was taken off treatment after 1 cycle due to toxicity. DLTs included febrile neutropenia (grade 3, n=2), syncope (grade 3, n=2) and vomiting (grade 3, n=1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was found to be too toxic. Eight patients had disease progression, median number of cycles was 1 (range 1-4), and median time to progression was 1 month (range 1-3). No treatment responses were noted and it was decided to stop accrual rather than explore lower dose levels. Associated with significant toxicities. Conclusions: The combination of dinaciclib and epirubicin does not appear to be an effective treatment option for TNBC, and is associated with significant toxicities. Clinical trial information: NCT01624441. [Table: see text]
Rates of appropriate genetic testing referral for breast cancer patients treated in a multidisciplinary cancer care setting.
Authors: Gomez Caitlin Laurel , Dawson Nicole Ann , Dvorak Robyn Lynn , Foster Nova , Hoyt Anne , Hurvitz Sara A. , Kusske Amy , Tseng Charles Y. , McCloskey Susan Ann 
Published: February 2017

45 Background: Approximately 5% to 10% of women diagnosed with breast cancer have a genetic predisposition, which can affect management recommendations. The National Comprehensive Cancer Network (NCCN) has established guidelines for genetics referral and testing, however recent publications have indicated low rates of family history documentation and appropriate genetics referral. We sought to assess the impact of standardized family history documentation on rates of appropriate genetics referral in a multidisciplinary breast clinic (MDC) setting. Methods: In advance of MDC consultation, women with newly diagnosed breast cancer complete an intake questionnaire which includes documentation of Ashkenazi Jewish ancestry along with a thorough family history. We retrospectively analyzed family history documentation to inform eligibility for genetic testing and rates of appropriate genetics referral. Results: Between June 2012 and April 2014, 202 women with newly diagnosed, nonmetastatic breast cancer were seen in MDC. We noted 100% compliance with family history documentation. Per NCCN Guidelines, genetic testing was indicated in 52% (106 patients), of which 77% were appropriately referred to a genetic counselor for evaluation. All patients who met criteria based on personal history factors including age ≤ 45, triple-negative disease under age 60, or two or more breast primaries under age 50 were appropriately referred. Patients who were eligible but not referred ranged in age from 46 to 93 and were eligible for testing based on Ashkenzi Jewish ancestry (3 patients) or family history factors including a relative with ovarian cancer (3 patients), ≥2 relatives with breast cancer (5 patients), or a relative with breast cancer < age 50 (7 patients). Conclusions: Compared with recently published national averages, rates of appropriate family history documentation and genetic testing referrals are significantly higher in our MDC setting. However, this analysis has identified significant opportunity for improvement via identification of overlooked referral indications. Initiatives are underway to improve future compliance.
Evaluation of the BRCA1 and BRCA2 mutation prediction models in Japanese patients with breast cancer.
Authors: Yoshida Reiko , Yotsumoto Junko , Watanabe Chie , Nakamura Seigo 
Published: February 2017

46 Background: The breast cancer genetic risk models for predicting BRCA1/2 mutation are widely used before genetic testing. BRCAPRO and Myriad II are common in Europe and America, and KOHBRA BRCA risk calculator (KOHCal) is utilized in the Asian model. However, it is unknown whether these mutation prediction models are useful in Japanese. In this study, we evaluated the accuracy of BRCAPRO, Myriad II and KOHCal in Japanese patients with breast cancer. Methods: We compared sensitivity and specificity with the 10% cut off value in 131 patients with breast cancer who underwent comprehensive BRCA1/2 genetic testing at Showa University Hospital between 2011 to 2014. All patients met the genetic testing criteria of NCCN Guidelines (Genetic/Familial High-Risk Assessment: Breast and Ovarian ver.1 2014) and were received counseling before genetic testing. We assessed validity of each model by constructing receiver operating characteristic (ROC) curves, and evaluating the area under each ROC curve (AUC). The carrier probabilities of BRCA1/2 with Myriad II were calculated using BRCA risk calculator from the Myriad company1), with BRCAPRO using the CancerGene software program (version 6.0) from the University of Texas South-western Medical Cernter2), and with KOHCal using KOHBRA BRCA risk calculator from the KOHBRA Study website (www.kohbra.kr)3). Results: DNA analysis identified 31 deleterious mutations (23.7%) and 10 unclassified variants (7.6%). The sensitivity of KOHcal (87.1%) was higher than BRCAPRO 67.7%) and Myriad II (72.2%) . BRCAPRO (AUC=0.882) had higher diagnostic accuracy than KOHCal (AUC=0.810) and Myriad II (AUC=0.763). KOHCal might be most suitable model to pick up patients for further genetic testing because it’s sensitivity was higher than Myriad II and BRCAPRO, although it had lower specificity than the other. Conclusion: Our results suggest that BRCAPRO and KOHCal are useful in Japanese patients with breast cancer for decision making for further genetic testing for BRCA1/2 mutations.
Tumor and systemic immune responses to preoperative (pre-op) cryoablation (cryo) plus immune therapy with ipilimumab (ipi) in early-stage breast cancer (ESBC).
Authors: Page David B. , Yuan Jianda , Ginsberg Arielle , Dong Zhiwan , Wong Phillip , Emerson Ryan , Sung Janice S. , Comstock Christopher , Solomon Stephen Barnett , Sacchini Virgilio , Morrow Monica , Brogi Edi , Morris Elizabeth Ann , Patil Sujata , Robins Harlan , Wolchok Jedd D. , Hudis Clifford A. , Norton Larry , Allison James Patrick , McArthur Heather L. 
Published: February 2017

64 Background: In mice, tumor cryo plus immunologic checkpoint blockade generates tumor antigen release, proliferation of tumor-specific T-cells, and enhanced survival. We previously demonstrated in a pilot study that pre-op cryo+ipi is well tolerated in women with ESBC and did not delay standard of care surgical resection. Here, we analyze pilot study tissue and blood to explore immune response. Methods: 18 ESBC patients (pts) were treated with preop cryo (n=6), single-dose ipi 10mg/kg (n=6), or cryo+ipi (n=6). As a potential surrogate for tumor immunogenicity, baseline T-cell tumor infiltrating lymphocyte (TIL) density was evaluated by T-cell receptor quantitative DNA sequencing. We explored the systemic immune response to cryo and/or ipi using previously described laboratory measures including inducible costimulator (ICOS, a marker of activated CD4+ T-cells) and plasma interferon gamma (IFNγ, a cytokine associated with T-cell activity). Results: Of the 18 study pts, 13 pts had hormone receptor-positive (HR+) disease, 2 pts had HER2+ disease (both treated with ipi alone) and 3 pts had triple-negative (TN) disease (1 ipi alone and 2 cryo/ipi). Baseline TIL density was highly variable overall (range 2-30%), but higher in HER2+ and TN pts (median 15%) compared with HR+ pts (median 5%). Sustained >2-fold elevations in ICOS and IFNγ were observed in the majority of cryo+ipi pts 30 days following treatment (ICOS: 5/6 pts; IFNγ: 4/6 pts), but in the minority of ipi pts (ICOS: 2/6 pts; IFNγ: 2/6 pts) or cryo pts (ICOS: 0/6 pts; IFNγ: 0/6 pts). Sustained ICOS and IFNγ elevations were observed regardless of baseline TIL density. Conclusions: Cryo+ipi was more likely to induce systemic immune activation compared to cryo or ipi alone. These potentially beneficial immune effects were observed in both HR+ and HR- subtypes, as well as in tumors with low or high baseline TIL density. These data support further studies of cryo+ipi in ESBC across HR+ and HR- subtypes, as well as in tumors that do not appear immunogenic at baseline.
Sources of information on decisions regarding contralateral prophylactic mastectomy: A prospective study.
Authors: Yao Katharine , Wroblewski Kristen , Van Haitsma Martha , Rabbitt Sarah , Williams Jordan , Kulkarni Swati 
Published: February 2017

75 Background: The rate of contralateral prophylactic mastectomy (CPM) has increased but little is known about the sources of information women utilize to choose CPM. Methods: A 55-item survey validated with breast cancer survivors was administered to 136 patients before surgery from two institutions. Results: The median age was 58 years (range 30-85). Eighty-three (69.2%) were White. Seventy-five (58.6%) had a lumpectomy, 41 (32%) a unilateral mastectomy and 12 (9.4%) had a CPM. About 80% of women felt the information they were given about breast cancer treatment was consistent. Fifty-five patients (41.7%) sought out extra information beyond what the doctor gave them. Information with the strongest influence was websites, books recommended by their doctor (44%) and websites, books not recommended by their doctor (30.4%) was the second strongest influence. Women ranked their doctor’s spoken advice as the most important source of information (74.3%) compared to advice from individuals outside of medicine, online information, observing breast cancer survivors and advice from friends/family. Plastic surgeons and the spouse/partner had more influence on those <50 years old compared to >50 years old (p=0.03). When asked which individual outside of medicine influenced their decision, women chose breast cancer survivors as their top choice compared to their spouse/partner, church leaders and friends/relatives. However, 82 women (62.6%) stated that information provided by staff did not include any information about removing the healthy breast. Forty-one (36%) stated that no one discussed contralateral breast cancer risk and 67 (59%) stated that no one talked with them about the possibility that cancer could turn up somewhere else even if both breasts were removed. Conclusions: Women do not always receive information about CPM from their doctors but they still highly value their doctor’s advice. These findings highlight an opportunity for physicians to educate women about the utility of CPM as part of their surgical treatment.
The effect of margin status and molecular subtype on women with invasive breast cancer treated with breast-conservation therapy.
Authors: Forrester Jared , Currey Adam D. , Tuyishimire Bonifride , Lin Jonathan , Kong Amanda L. 
Published: February 2017

83 Background: A consensus statement was recently published by SSO/ASTRO on margins for stage I and II invasive breast cancer treated with breast conserving surgery (BCS). We examined patients with invasive breast cancer who underwent BCS to determine if margin status and molecular subtype influence outcomes. Methods: We the reviewed charts of 754 Stage I-III breast cancer patients treated with BCS from 2003-2010. Margin status was defined as negative ≥ 2mm, close < 2mm and positive as tumor on ink. Conventional receptor analyses were used as markers for molecular subtype classification (luminal A, luminal B, Her2 positive, and basal). Clinicopathologic variables were tested using the Fisher’s exact, Chi-square, ANOVA F-test, and Kruskal-Wallis tests. A Cox proportional - Hazards model was used to measure the impact of these variables on locoregional recurrence (LRR), breast cancer-specific (BCSS) and overall survival (OS). Results: The median age of the cohort was 58 (range 27-89 years). Most were white (88%), had T1 tumors (76%), luminal A tumors (66%), invasive ductal histology (80%), and were node negative (76%). Of the 754 patients, 26% had close margins, 2% positive margins, and 9% unknown margins. With a median follow-up of 5.2 years, OS was 92%. Twenty eight patients had a LRR with a median time to recurrence of 5.1 years. On multivariate analysis, molecular subtype, pathologic grade (p=0.01), and use of radiation (p<0.0001) were the only significant predictors of LRR. Unknown subtype, compared to Luminal A, was less likely to have a LRR (p=0.04). Basal (p=0.0002), Her2+ (p=0.03), Luminal B (p=0.002) and unknown subtype (p=0.04) had worse BCSS compared to Luminal A tumors. Margins had no impact on LRR or BCSS but those with close margins and unknown margins had worse OS compared to negative margins (p=0.01, p=0.007). Variables predictive of OS were margins, age, race, node status, chemotherapy, anti-endocrine therapy, and radiation. Conclusions: In this cohort treated with BCS, molecular subtype was a predictor of LRR and BCSS but not OS. Margin status did not impact LRR and BCSS. Although margin status was a predictor of OS, tumor biology remains the significant determinant of outcome.