bluuebunny/crossref_metadata_2025 huggingface dataset:
Pilot study of proton therapy for treatment of regional lymphatics in patients with breast cancer.
Authors: Bradley Julie Ann , Dagan Roi , Ho Meng Wei , Xu Natalie , Morris Christopher G. , Li Zuofeng , Mendenhall Nancy P.
Published: February 2017

100

Background: To determine the feasibility of proton therapy (PT) for regional nodal irradiation (RNI) in women with breast cancer and to compare target coverage and normal tissue avoidance between PT and conventional radiation. Methods: From May 2012 to May 2013, 14 women were prospectively enrolled in this pilot study; 5 had right-sided and 9 had left-sided. Median age at the time of PT was 53.7 years (range 37-73). The breast or chest wall and supraclavicular, axillary, and internal mammary (IM) lymph nodes were treated in all patients. Proton and conventional plans were developed for each patient; the superior plan, as defined by organ at risk sparing and target coverage, was treated. Targets and normal tissues were delineated on treatment CT scans. Wilcoxon signed rank sum test was used to compare dose-volume parameters. Results: For all 14 patients, the proton plan better met the dosimetric goals, and was used for treatment delivery. Median heart V5 measured 0.8% for the proton plans versus 23% for the conventional plans (p=0.0005). Median mean heart dose measured 0.55 Gy (range 0– 3.2Gy) for the proton plans versus 4.9 Gy (range 2-9.1 Gy) for the conventional plans (p=0.0005). Significant difference in median lung V5 and median V20 were found: 41% and 24% for the proton plans and 67% and 38% for conventional plans, respectively. PTV breast/chest wall coverage was adequate with both plans. Coverage of the level II axilla was higher in the proton plans (D95 48 Gy vs 44 Gy, p=0.01) as was coverage of the IM nodes (D95 50 Gy vs 46 Gy, p=0.01). Acute toxicity data is available for 12 patients. The most common acute toxicity was radiation dermatitis, with 9 patients experiencing grade 2 and 3 patients experiencing grade 3 toxicity. Other grade 2 toxicities included fatigue (n=3), pain (n=2), esophagitis (n=4), and skin infection (n=1). Radiation dermatitis was the only grade 3 toxicity. No grade 4 or 5 toxicities developed. Conclusions: Adjuvant PT is a well-tolerated, technically feasible modality for RNI, with a significant decrease in cardiac V5, V20, and mean heart dose as well as lung V5 and V20. Further investigation of PT for RNI in breast cancer is warranted to improve the therapeutic ratio by decreasing radiation exposure to the heart and lung. Clinical trial information: NCT01365845.
Are high mastectomy rates associated with unwanted variation in other aspects of breast cancer treatment? An overview of practice patterns in Alberta, Canada in 2009-2010.
Authors: Morrissey Sarah , Quan May Lynn
Published: February 2017

102

Background: The Canadian Partnership Against Cancer recently released a system performance report identifying large variation in breast cancer treatment across Canada. Contrary to provincial guidelines, Alberta had higher than average rates of mastectomy (56%); however, factors driving this variation remain unknown. We sought to (1) determine if practice patterns of primary breast surgery and adjuvant therapy adhered to guidelines and (2) to describe influencing factors on treatment practices between the two major cancer programs in Alberta to inform future knowledge translation strategies for guideline implementation. Methods: All patients diagnosed with breast cancer (ICD 9-174) between January 2009 and December 2010 were identified from the Alberta Cancer Registry. Demographic, surgical, treatment, and pathology data were abstracted from the electronic health record. Descriptive statistics and t-testing comparing mastectomy rates, axillary surgery and adjuvant therapy between the two major cancer programs were performed. Results: There were 2,817 surgeries for early breast cancer in the study cohort between 2009 and 2010. Conclusions: Practice patterns identify variance from current guidelines. Mastectomy rates are influenced by surgeon volume and tumor size. Management of positive SN and adjuvant therapy is variable and may reflect under treatment. Further investigation of drivers for mastectomy and adjuvant therapy are necessary. [Table: see text]
Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (ESBC): Predictors of cognitive decline.
Authors: Rugo Hope S. , DeLuca Amy N. , Heflin Lara , Fang Sally , Melisko Michelle E. , Moasser Mark M. , Park John W. , Chien Amy Jo , Munster Pamela N. , Esserman Laura , Landau Susan M. , Jagust William J. , Kramer Joel H.
Published: February 2017

104

Background: Cog complaints are common among women receiving adjuvant therapy (Rx) for ESBC. Longitudinal prospective data is needed to help identify predictors of cog decline. We conducted a prospective trial to evaluate the effects of chemo- (CTX) and hormone therapy (HRx) on brain and cog fcn in pts with ESBC using multiple objective and subjective tests as well as MRI/PET imaging. Here we report evaluation of clinical characteristics that predict decline in cog fcn. Methods: Eligibility included female patients (pts) planning to receive adjuvant Rx for ESBC. Pts were enrolled in 3 Rx groups (grps): CTX, CTX and HRx, and HRx, with a 4th no Rx age/education matched control grp. All pts underwent a battery of objective and subjective cog tests before start of Rx, 1 mo after CTX or 5 mo after start of HRx (FU1), then 9 mo (FU2) and 18 mo (FU3) after CTX. Brain MRI, PET and serum estradiol (E) were performed at baseline, FU1 and FU2. Results: 81 pts were enrolled as follows, 14 CTX, 33 CTX and HRx, 22 HRx, 12 control. 90% completed FU1, 72% FU2, and 62% FU3, with 29 pts waiting to complete testing. Demographics were similar between grps, median age 54, 78% Caucasian. At each FU, ~25% of pts showed decline in cog fcn compared to the prior time point using a reliable change index; 51% showed decline at > 1 time point, primarily in tests measuring executive function and verbal memory. 62% of pts who declined from baseline to FU1 later stabilized or improved; 77% of pts who declined from FU1 to FU2 later stabilized or improved. Compared to controls, receipt of CTX and HRx (OR 3.15, p=.008), or HRx overall (OR 4.94, p=.004) but not serum E, menopausal status, or CTX, were significant predictors of decline at any time point. Rx group did not predict poorer perceived cog fcn (FACT-COG); depression and fatigue did not predict decline in objective cog fcn. Conclusions: Decline in cog fcn is common in pts receiving adjuvant Rx for ESBC. Predictors included CTX and HRx, or HRx overall but not other treatment and pt related factors. Ongoing HRx, particularly after CTX, appears to be a risk factor for worse cog fcn. Pts should be aware that HRx may be a risk factor for cog deficits, and intervention studies should be designed to focus on this group of pts. Funding: NIH R01 1AG025303-01A2. Clinical trial information: 00755313.
Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (BC): Relationship between perceived and measurable cognitive deficits.
Authors: Heflin Lara , Fang Sally , DeLuca Amy N. , Melisko Michelle E. , Moasser Mark M. , Park John W. , Chien Amy Jo , Munster Pamela N. , Landau Susan M. , Jagust William J. , Kramer Joel H. , Rugo Hope S.
Published: February 2017

105

Background: Cognitive complaints are common among patients (pts) receiving adjuvant therapy (Rx) for early stage BC. Longitudinal prospective data is needed to help understand the relationship between measured cog fcn, patient reported cognitive changes, and patient reported depression and fatigue. We conducted a prospective trial to evaluate the effects of chemo- (CTX) and hormone therapy (HRx) on brain and cog fcn in pts with early stage BC using multiple objective and subjective tests as well as MRI/PET imaging. Here we report relationships between objective measures and patient reported outcomes (PRO). Methods: Eligibility included female pts planning to receive adjuvant Rx for ESBC. Pts were enrolled in 3 Rx groups (grps): CTX, CTX and HRx, and HRx, with a 4thno Rx age/education matched control group. All pts underwent a battery of objective and subjective cog tests before start of rx, 1 mo after CTX or 5 mo after start of HRx (FU1), then 9 mo (FU2) and 18 mo (FU3) after CTX. Brain MRI, PET and serum estradiol were performed at baseline, FU1 and FU2. Results: 81 pts were enrolled as follows: 14 CTX, 33 CTX and HRx, 22 HRx, and 12 control. 90% completed FU1, 72% FU2, and 62% FU3, with 29 pts waiting to complete testing. Demographics were similar between grps, median age was 54 (range 34-71), 78% were Caucasian. At FUP1, depression (BDI-II) and fatigue predicted poorer overall perceived cog fcn (FACT-Cog); decline in letter fluency (FAS) on cog testing also predicted poorer overall perceived cog fcn (FACT-Cog). Decline in verbal memory (CVLT-II) predicted perceived memory deficits (FACT-Cog Memory), even after controlling for depression and fatigue. Conclusions: In pts receiving adjuvant Rx for early stage BC, depression, fatigue, and decline in letter fluency predicted poorer perceived cog fcn. Decline in verbal memory independently predicted perceived memory deficits, demonstrating that PRO are related to actual deficits in cog fcn. Future intervention studies should focus on these factors. Funding: NIH R01 1AG025303-01A2. Clinical trial information: 00755313.
Patient experiences and preferences for survivorship care.
Authors: Mitchell Kelly Westbrook , Houck Kevin , Kimmick Gretchen Genevieve , Trotter Kathy J. , Peppercorn Jeffrey M.
Published: February 2017

110

Background: The optimal method for delivery of care to over 2 million breast cancer survivors in the U.S. remains unclear, with multiple models currently in practice. This study involved a patient-centered investigation of experiences and preferences for breast cancer survivorship care. Methods: We conducted a single-institution, cross-sectional, self-administered survey of needs, experiences, and interests following initial breast cancer care at an academic multidisciplinary breast clinic. For 4 weeks, all patients presenting for routine oncology care were provided a survey at appointment check-in. Analysis is descriptive, with chi square testing used to evaluate demographic correlates of response. Results: 612 surveys were distributed, with a response rate of 66.8%. Median age of respondents was 56 (range 26-93); 71% were white, and 18% identified themselves as black. Over 55% had a college degree. Regarding ongoing care, 63% preferred to see a cancer specialist at least annually, and 30% wanted access to a cancer specialist as needed. Less than 15% preferred referral to a local practice, and less than 15% favored follow-up care from a specialized cancer survivorship clinic. Regarding visit content, over 90% felt assessment for disease recurrence was a priority on follow-up. A majority were interested in emotional and psychological support (52%). Nearly 40% of patients felt that assistance with non-cancer related health issues was very important in oncology clinic follow-up, but only 25% wanted a cancer specialist to provide general medical care. 42% reported receiving a summary of their cancer treatment. 37% reported receiving awritten plan or list of recommendations regarding care needed as a cancer survivor. White patients were less likely than non-white patients to receive a treatment summary (p < 0.02) or a care plan (p<0.005). Age and education were not correlated with receipt of these materials. Conclusions: Patients’ experiences and preferences regarding long-term management of breast cancer are varied. Many patients desire ongoing follow-up with their primary oncology team. Further evaluation of patients’ goals, needs, and an evidence-based approach to follow-up care is needed to guide optimal program design.
Mammography screening among women 40-49 years old, before and after USPSTF guideline changes.
Authors: Hsu John , Huang Jie , Fireman Bruce
Published: February 2017

113

Background: The age at which to start breast cancer screening is controversial. The US Preventive Task Force (USPSTF) recommended against routine mammography screening in women 40-49 years old in November 2009 (the 2002 report had recommended screening), and instead suggested that women consult their physicians. We examined the frequency of screening among 40-49yo, and characteristics of the screened. Methods: We examined mammography screening among 85,650 women who were continuously enrolled in a prepaid integrated delivery system and who were between 40-45yo in 2006. We excluded women with any cancer diagnosis (2005-2009). Using logistic regression, we examined the association between screening in 2010 and several traits, e.g., mammogram cost-sharing, screening behavior before 2010, comorbidity score, race/ethnicity, and neighborhood socio-economic status indictors. In 2010, 75% of women had free mammograms; for the others, the median cost-sharing amount was $10. Results: Nearly all subjects (92%) received at least one mammogram between 2006-10: 14% received one; 37% received two; 33% received three; 6% received four; and 1% received 5+ mammograms. The unadjusted percent screened during each year increased slightly from 2006-2009 (38% to 47%) before dropping in 2010 (45%). Among women screened before the guideline changes, 47% received a mammogram in 2010. After adjustment, subjects who had any cost-sharing (OR=0.96 vs. free screening, 95%CI: 0.93-0.99) or who lived in lower SES neighborhoods (OR=0.94 vs. higher SES, 95%CI: 0.90-0.97) were less likely to receive a screening mammogram in 2010. Subjects with frequent earlier screening (e.g., OR=4.44 for four mammograms vs. none, 95%CI:3.99-4.94) and who were Asian (OR=1.05 vs. White, 95%CI: 1.01-1.09) were more likely to receive a 2010 mammogram; Black and Hispanic subjects had similar odds as Whites. Conclusions: In this integrated system, mammography screening among women 40-49 years old decreased slightly after the 2009 USPSTF recommendation against routine screening. Better alignment of insurance benefits with screening guidelines could improve adherence with recommendations.
Breast cancer patients with diabetes mellitus: Defining the population and assessing outcomes.
Authors: Karlin Nina J. , Dueck Amylou C. , Nagi Reddy Sravan K. , Verona Patricia M. , Cook Curtiss B.
Published: February 2017

137

Background: Diabetes has been associated with an increased risk of mortality among patients with many types of cancers. Methods: We performed a case-control study of 109 breast cancer patients to determine the impact of diabetes on disease recurrence and survival. These 109 patients diagnosed with invasive breast cancer during 2007-2011 with diabetes were identified from the institutional Cancer Registry and matched to 109 breast cancer patients without diabetes according to age, race/ethnicity and year of diagnosis. Statistical tests included paired t-tests, McNemar’s tests, and stratified Cox regression. Results: The median ages of those with and without diabetes were 68 years, and 91% in both groups were white (both matched). Patients with and without diabetes were not significantly different in terms of tumor grade, cancer stage, estrogen or progesterone receptor status, HER2 neu status, marital and employment status, smoking use, use of adjuvant chemotherapy, and steroid treatment (all P >.4). Patients with diabetes reported less use of alcohol (50% vs 64%, P=.04), and had greater BMI (79% overweight/obese vs 58%, P= .002). Survival analysis demonstrated no differences in survival from initial breast cancer diagnosis (HR=1.25, 95% CI 0.49-3.17) with median follow-up of 2.2 years (range 0.1-4.9), and no differences in recurrence-free survival (HR=1.00, 95% CI 0.14-7.10) though very few deaths and recurrences were observed. Within the diabetes group, 96 (88%) had type 2 diabetes and 97/106 (92%, 3 unknown) had diabetes pre-existing to cancer diagnosis. Initial diabetes therapy included diet (33, 30%), oral therapy (48, 44%), insulin (21, 19%), or oral+insulin (6, 6%). 7 patients required a change in diabetes therapy within 1 year of cancer diagnosis with 3 patients starting insulin. 32/70 (46%) with available lab data had 1 or more A1C >/=7 within 1 year of cancer diagnosis. Conclusions: In this retrospective, carefully matched case-control study, we developed a comprehensive profile of the patient population with newly diagnosed breast cancer and diabetes. Diabetes did not appear to impact mortality or recurrence-free survival based on descriptive estimates in this small breast cancer cohort.
Neoadjuvant single and dual HER2 blockade among patients with localized HER2-positive breast cancer.
Authors: Reynolds Kerry Lynn , Cheng XingXing , Bhatia Ashmeet , Specht Michelle Connolly , Smith Barbara Lynn , Moy Beverly , Bardia Aditya
Published: February 2017

147

Background: Dual neoadjuvant HER2 directed therapy is offered only in a clinical trial setting and is not standard of care, but emerging data suggests targeting multiple mechanisms may be more effective. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant dual and single agent HER2 blockade on breast conserving surgery (BCS), and on pathological complete response (pCR) for estrogen receptor (ER)+ and ER- tumors, as well as the impact of pCR on disease-free survival (DFS) and overall survival (OS) for HER2+ breast cancer. Methods: MEDLINE, EMBASE, and Cochrane Controlled Clinical Trials Register databases were queried to identify eligible trials. Inclusion criteria were prospective, neoadjuvant trials that had at least one arm with HER2 directed therapy, and reported pCR. Pooled relative risk ratios (RRs) and p values were estimated for endpoints using the random effects statistical model. Results: We identified 36 trials (N = 4130). High pCR rates (> 40%) were seen with anthracycline-based chemotherapy and trastuzumab alone, and non-anthracycline based dual HER2 blockade. The addition of trastuzumab to chemotherapy did not improve BCS rate (RR 1.40, p = 0.15), but significantly increased rates of pCR (RR 1.91, p = 0.0001). Similarly, dual HER2 blockade compared to trastuzumab alone did not improve BCS rate (RR 1.03, p = 0.84), but significantly increased rates of pCR overall (RR 1.39, p < 0.00001), in both ER+ (RR 1.72, p = 0.01) and ER- subsets (RR 1.91, p = 0.0001), with no increase in grade 3/4 toxicity (RR:1.13, p = 0.16). Dual HER-2 blockade without chemotherapy was associated with pCR in a subset (11.2% - 27%) with minimal toxicity (incidence of grade 3/4 toxicity:1-5%). Higher pCR was associated with improved DFS (RR 2.29, p = 0.006) and OS (RR 4.61, p = 0.009). Conclusions: Neither the addition of trastuzumab to chemotherapy, nor the dual-HER2 blockade compared to trastuzumab, improves rates of BCS. However,both significantly improve rates of pCR, which is associated with improved DFS and OS. Dual HER2 blockade,with endocrine therapy for ER+, could potentially lessen or even obviate the use of chemotherapy.
Phase I study of the HDAC inhibitor vorinostat in combination with capecitabine in a biweekly schedule in advanced breast cancer.
Authors: James Edward Samuel , Chung Gina , Sowers Noelle Marie , Clark Mary Beth , Lilian Rebecca , Abraham Gineesha , Chmael Susan , Cappiello Michelle , DiGiovanna Michael , Hofstatter Erin Wysong , Sanft Tara Beth , Israel Gary M. , Pusztai Lajos , Harris Lyndsay , Abu-Khalaf Maysa M.
Published: February 2017

154

Background: Synergy between histone deacetylase inhibitors and 5-fluorouracil is thought to be due to down regulation of thymidylate synthase. Study objectives are to assess maximum tolerated dose (MTD), dose limiting toxicities (DLT) and objective response rate of vorinostat (V) in combination with capecitabine (C). Secondary aims are pharmacodynamics of V. Methods: Cohorts of 3-6 patients (pts) were enrolled on a 3+3 dose-escalation phase to assess MTD of escalating doses of oral C (1500/1800/2000mg) with V 200 mg BID on days 1-7 and 15-21 of a 28 d cycle. 10 pts enrolled on dose expansion phase and treated at MTD. Pts received a “run in” treatment of V for 5 d and pre/post V biopsy (bx) collected when feasible. DLT was defined as ≥ grade 3 non hematological toxicity, grade 4 thrombocytopenia, grade 4 neutropenia > 5 d, grade 4 febrile neutropenia requiring hospitalization, QTc >500ms,or treatment delay > 2 weeks from toxicity. Microarray analysis was performed using Illumina HT-12 gene arrays on pre/post bx from 4 pts. Results: 23 ptswith median age 51 (range 33-69) were treated: 8 pts at 1500/200mg, 5 pts at 1800/200mg, and 10 pts treated on dose expansion phase at 1500/200mg. Median # of prior lines of chemotherapy was 2 (range 0-7). 3 pts are still on study. Median # of cycles on study were 2 (range 1-42). Cycle 1 DLT was grade 3 fatigue in 2 pts treated on 1800/200mg, and in 1 pt treated on 1500/200mg. Other grade 3/4 toxicities are summarized in the Table. 14 pts are evaluable for response (12 pts at 1500/200mg and 2 pts at 1800/200mg). No objective responses were seen, 3 pts had stable disease > 6 months (1 pt completed 42 cycles). All post V bx converged on principal components analysis. Changes in pathways involved in extracellular matrix and TGFb pathway were noted. Conclusions: DLT of C concomitant with V was fatigue. MTD was 1500 mg C combined with 200 mg V BID. Combination has modest clinical activity. Gene expression profiles suggest consistent pathway modulation with V. Clinical trial information: NCT00719875. [Table: see text]
Patient-reported physical, emotional, and social functioning in advanced breast cancer: Insights from BOLERO-2.
Authors: Yardley Denise Aysel , Hortobagyi Gabriel N. , Lebrun Fabienne , Beck J. Thaddeus , Neven Patrick , Baselga Jose , Petrakova Katarina , Dakhil Shaker R. , Sabatini Silvia , Komorowski Anna , Chouinard Edmond Emilien , Young Robyn R. , Gnant Michael , Pritchard Kathleen I. , Zhang Jie , Ziemiecki Ryan , Brechenmacher Thomas , Taran Tanya , Sahmoud Tarek , Noguchi Shinzaburo
Published: February 2017

155

Background: The phase III BOLERO-2 study at 18 months’ median follow-up showed that everolimus (EVE) + exemestane (EXE) significantly improved progression-free survival (PFS) vs EXE alone in 724 patients with hormone receptor–positive (HR+) advanced breast cancer (ABC) with recurrence/progression during/after nonsteroidal aromatase inhibitor (NSAI) therapy. A higher rate of grade 3/4 adverse events was noted with EVE + EXE but was not associated with deterioration in quality of life (QOL) based on the EORTC QLQ-C30 Global Health Status scale. Additional patient-reported post hoc analyses of QOL are reported herein. Methods: During BOLERO-2, QOL (EORTC QLQ-C30 and QLQ-BR23) was assessed at baseline and q 6 wk thereafter until progression or discontinuation. Physical, emotional, and social functioning subscales of QLQ-C30 were analyzed. Time to definitive deterioration (TTD) was defined based on either a 5% (protocol-specified) or a 10-point (more stringent) decrease from baseline for each subscale and analyzed by Kaplan-Meier methods. The difference between treatments was assessed by a log-rank test stratified by randomization factors. Results: QLQ-C30 compliance was >80% at week 48. Among the 3 protocol-specified QLQ-C30 subscales, analyses based on a 5% decrease in QOL showed a longer TTD for both physical and emotional functioning in the EVE + EXE group vs EXE alone (log-rank p = 0.0120 and p = 0.0277, respectively). The TTDs for social functioning were similar in both treatment arms (log-rank p = 0.3374). Analyses based on a 10-point decrease indicated a longer TTD for physical functioning in the EVE + EXE group (15.2 mo) vs EXE alone (9.7 mo; log-rank p = 0.0211). The TTDs for emotional and social functioning were similar between EVE + EXE and EXE alone: 13.9 vs 13.8, respectively (log-rank p = 0.4023), and 11.5 vs 9.5, respectively (log-rank p = 0.2507). Conclusions: The treatment goal for ABC is to maximize clinical benefit with minimal negative effects on QOL. These additional BOLERO-2 QOL analyses confirmed that the more than doubling of PFS with EVE + EXE was accompanied by maintained physical, emotional, and social functioning compared with EXE alone in patients with HR+ ABC progressing after NSAI. Clinical trial information: NCT00863655.
Trastuzumab emtansine (T-DM1) in previously treated HER2-positive metastatic breast cancer (MBC): Results from an expanded access study.
Authors: Yardley Denise Aysel , Krop Ian E. , LoRusso Patricia , Robert Nicholas J. , Mayer Musa , Abidoye Oyewale O. , Lai Catherine , Yoo Bongin , Perez Edith A.
Published: February 2017

166

Background: T-DM1 is an antibody-drug conjugate composed of trastuzumab, a stable linker, and the cytotoxic agent DM1. Few T-DM1 data are available in settings approximating clinical practice. We present safety and efficacy data from T-PAS, an expanded access study of T-DM1 in patients (pts) with previously treated HER2-positive MBC. Methods: T-PAS is a US multicenter study of T-DM1 (3.6 mg/kg q3w) in HER2-positive (IHC 3+ or FISH/CISH+) locally advanced or MBC. Key eligibility criteria: prior anthracycline and taxane; prior capecitabine or 5-FU and ≥2 HER2-directed agents (including trastuzumab and lapatinib) for MBC; LVEF ≥50%. Primary endpoint: safety; secondary endpoint: investigator-assessed objective response rate (ORR) in pts with measurable disease. Safety was assessed on day 1 of each cycle; ECHO/MUGA scans were every 12 weeks. Results: This analysis includes 215 pts enrolled in May 2010–Sep 2011 (data cutoff 7/31/2012). Pts received a median of 7 prior systemic MBC therapies (range 1–23) with a median cumulative anthracycline dose of 240 mg/m2(range 6–2645). At baseline, median LVEF was 60% and 50% of pts had investigator-reported cardiovascular disease. Median follow-up was 5.9 months (range 0.1–25.3); median T-DM1 duration was 5.0 months (range 0–23) with 15.8% receiving >18 cycles. ORR was 25.6% (42/164). Rate of grade ≥3 AEs was 43.7% and of SAEs of any grade was 18.1%. Most common all-grade AEs were fatigue (50.7%), nausea (36.3%), and headache (24.2%). Most common grade ≥3 AEs were thrombocytopenia (7.9%), fatigue (4.7%), and increased aspartate aminotransferase and anemia (each 3.7%). There were no grade ≥3 bleeding events. Cardiac dysfunction (primarily asymptomatic decreases in LVEF) was reported in 8 pts (3.7%); 4 were grade ≥3, 3 resulting in T-DM1 discontinuation. Conclusions: In this study that more closely reflects the real-world setting, the safety profile of T-DM1 was similar to that previously reported in conventional clinical trials, with no new safety signals. In this pretreated population (median of 7 prior therapies for HER2-positive MBC), significant activity was observed. Clinical trial information: NCT01120561.
Kinase-sensing system to identify the oncogenic phospho-fingerprint of breast cancer.
Authors: Mori Miki , Chen Zhongzhong , Boudreau Aaron , van't Veer Laura , Coppe Jean-Philippe
Published: February 2017

23

Background: Kinases and their substrates harness myriad critical molecular pathways. A new highly valuable assay would be one detecting the true active state of phospho-signaling networks. To address this technological and knowledge gap, we developed a semi-high throughput sensing system that monitors the catalytic activity of kinases using peptides as phosphorylation targets/probes. We used this assay to evaluate the presence of dysfunctional kinases in biological extracts and identify oncogenic phospho-signatures prevalent in breast cancer. Methods: We developed a human kinase protein and peptide repertoire computationally curated from thousands of publications. Out of the 2,702 validated peptide targets and 6,173 kinase-substrate nodes we compiled, we chose a subset of 151 biological peptides predicted to specifically report on tyrosine / serine / threonine kinases, including EGFR, ERK, AKT, SRC, ABL. Along with 91 control peptides, we tested a total of 242 peptides in a luminescence ATP-consumption assay for their ability to report on the kinases’ activity. The assay was further validated using an isogenic culture model of basal like breast cancer (HMT-3522 S1 and T4-2), and cell lines harboring various oncogenic alterations (MDA-MB-231, MCF7, T47D, AU565, ZR75.1, SKBR3). Results: The differential phosphorylation activity of recombinant kinase enzymes was successfully detected in time course, dilution and inhibitor experiments. The increased presence of (hyper-) activated SRC, EGFR, AKT or ABL kinases observed by western blots in subsets of breast cancer cells, was selectively, repeatedly and specifically detected using the peptide-based kinase assay. Significantly altered peptide-phosphorylation patterns were successfully integrated into signatures using gene expression microarray-like analysis, revealing the breast cancer-associated map of phosphorylation circuits. Conclusions: This assay is suitable to comprehensively capture the activity of kinase signaling networks. We will now use this functional proteomic assay to identify the active, oncogenic kinome of breast cancer, with the objective to improve clinical guidance and individualize breast cancer patients’ therapy.
Cost-benefit of recurrence score–guided treatment using an Oncotype DX 21-gene assay: A single institution analysis.
Authors: Abbi Kamal Kant Singh , Shahid Nauman , Hameed Muhammad Khurram , Fink Brian , Gaba Colette , Mohamed Iman
Published: February 2017

29

Background: In 2010 the National Comprehensive Cancer Network recommended a 21-gene assay recurrence score (RS) to aid in the adjuvant treatment decision among patients with estrogen receptor positive, lymph node negative early stage breast cancer. Early-decision impact studies show that the RS can reduce overall chemotherapy use by 27%. This study was performed to assess the cost-benefit of the test for the patients diagnosed and treated an academic institute before 2010. Methods: Data from early breast cancer estrogen-receptor–positive and lymph-node–negative patients (n = 87), who were diagnosed and treated at our center from 2004-2010 were analyzed. All patients had the 21-gene recurrence test done to guide in their management. Cost of chemotherapy, adverse effects, and supportive care costs were calculated from previously published articles. Results: 66 patients with stage I breast cancer and 21 patients with stage II were analyzed. All but one patient had a tumor size more than 5mm. In total, 27 patients received chemotherapy. Characteristics of patients receiving chemotherapy are shown in the table. Cost of 21 gene recurrence score assay was $4,000. Savings for each patient who did not receive chemotherapy was $21,715 after accounting for cost of the test. The total savings for 60 patients who did not receive chemotherapy was $1,302,900. Conclusions: Use of the 21-gene assay in patients with early stage lymph node negative breast cancer improves health outcomes by avoiding chemotherapy-related adverse events. It also appears to add no incremental costs. This study emphasizes the cost-saving potential of the Oncotype Dx 21 gene assay. [Table: see text]
Breast cancer patients’ risk perceptions and treatment values following surgical consult.
Authors: Kaiser Karen , Cameron Kenzie A. , Stolley Melinda , Bethke Kevin P. , Hansen Nora M. , Jeruss Jacqueline Sara , Clayman Marla L. , Khan Seema Ahsan
Published: February 2017

36

Background: Contralateral breast cancer (CBC) is the most common second primary cancer in breast cancer patients. The 10-year risk of CBC for patients with locally invasive or intraductal disease is approximately 6%. However, a recent study reported that prior to surgical consult newly diagnosed breast cancer patients without a BRCA mutation estimated their 10-year CBC risk to be 31.4%. We sought to evaluate breast cancer patients’ perceived risk of future cancer and their treatment values following surgical consult. Methods: Women diagnosed with ductal carcinoma in-situ or stage I-III invasive breast cancer were interviewed in the period between surgical consult and surgical treatment. Participants completed the Perceived Risk Questionnaire (PRQ) and the Values Scale. The PRQ contains 5 questions to assess perceived likelihood of future cancer on a 5-point scale (1 = not at all likely, 5 = very likely). For each question, women also estimate the likelihood of cancer in the next 10 years as a percentage from 0 to 100. The Values Scale measures the importance of 11 treatment-related values (e.g., How important is it to you to keep your breast?) on a 10-point scale (1 = not at all important, 10 = very important). Results: Interviews were completed with 20 patients (mean age 54.7 years) without a known BRCA mutation. On the Values Scale, women identified minimizing the chance of cancer elsewhere in the body (mean=9.2), in the other breast (mean = 9.1), and in the same breast (mean = 8.8) as most important. Patients estimated their 10-year risk to be 13.6% for CBC, 14.2% for breast cancer appearing in the same breast, and 19.6% for cancer appearing elsewhere in the body. One-fourth of participants believed they faced at least a 50% chance of encountering breast cancer again in the next 10 years. Conclusions: Women in this study reported lower perceived risk of CBC than in a prior study of perceived risk prior to surgical consult, thus suggesting that the surgical consult may lead to a reduction in perceived risk. Nonetheless, participants’ estimated their 10-year risk of CBC to be twice the actual estimated risk. Our findings indicate a need for additional patient education about CBC risk.
The accuracy of preoperative U.S.-guided vacuum-assisted breast biopsy (VABB) in determining ER, PgR, HER2, and Ki67 status in early breast cancer.
Authors: Kamei Keitaro , Fujita Takashi , Ito Toshikazu , Yagata Hiroshi , Ono Minoru , Watanabe Ryoji , Gomi Naoya , Onishi Kiyoshi , Sakamoto Naomi , Hashimoto Hideyuki , Taguchi Tetsuya , Nakayama Takahiro ,   Japan Association of Breast and Thyroid Sonology (JABTS) Interventional Study Group
Published: February 2017

37

Background: The intrinsic subtypes are important in the management of patients with early breast carcinoma; however, there have been only a few reports about the accuracy of preoperative subtyping by the preoperative ultrasonography guided vacuum-assisted breast biopsy (U.S.-guided VABB). The aim of this study was to evaluate concordance of the status of ER, PgR, HER2, and Ki67 between U.S.-guided VABB and subsequent surgical specimen. Methods: We retrospectively assessed the concordance of ER, PgR, HER2 and Ki67 status between U.S.-guided VABB and surgical specimen. The patients (n=228) underwent surgical treatment without neoadjuvant chemotherapy at the institute of Japan Association of Breast and Thyroid Sonology (JABTS) Interventional study Group from 2009 to 2012. All the US-guided VABB were performed using 8 or 11-gauge Mammotome or 10-gauge VACORA. The ER and PgR status were determined by IHC and HER2 expression status was tested by both IHC and FISH. The agreement on ER, PgR, HER2 and Ki67 status were evaluated by the absolute concordance rate and the kappa statistic values. Results: The concordance rate of ER, PgR, and HER2 status between U.S.-guided VABB and surgical specimens were 96.4% (134/139), 89.2% (124/139), and 96.3% (130/135), respectively (kappa statistic value of 0.90, 0.77, and 0.84), and the agreement of Ki67 level was 89.6% (112/125) with a Kappa statistic value of 0.79. The concordance rate of the intrinsic subtypes was 84.0% (105 of 125 cases). Conclusions: The judgment of ER status, and HER2 status by preoperative U.S.-guided VABB can be used with confidence to determine the treatment strategies based on molecular subtypes.
Biomarkers predictive for pathologic response to neoadjuvant docetaxel/cyclophosphamide chemotherapy in primary breast cancer.
Authors: Shimada Kazuhiro
Published: February 2017

42

Background: Since docetaxel /cyclophosphamide chemotherapy (TC) has proven to be superior to anthracycline/cyclophosphamide (AC) in U.S. Oncology Research Trial 9735, TC has been widely used for treating patients with breast cancer. However, taxane-specific adverse events like neuralgia and edema can’t be ignored. Thus, we performed neoadjuvant study with TC to clarify biological markers of this regimen. Methods: 79 patients with invasive breast cancer received TC (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2, q3w for 4 courses) at the neoadjuvant setting and underwent surgical treatment. Before treatment, the clinic-pathological and immunohistochemical markers (ER, PgR, HER-2, Ki-67, p53, topoisomerase IIα, ClassIII β tubulin, CK5/6, EGFR) were examined with core-needle biopsy specimens. The correlation between the pathological response and expressions of markers was investigated. Results: 33 patients (41.8%) achieved quasi-pathological complete response (QpCR). Univeriate analysis revealed that ER (p < 0.001), PgR (p = 0.007), Ki-67 (p = 0.022) and classIII β tubulin (p = 0.032) were associated with QpCR. Only ER (p = 0.050) and classIII β tubulin (p = 0.028) remained with a statistical significance at multivariate analysis. Subgroup analysis revealed that the negativity of CK5/6 and/or EGFR was correlated with QpCR in the triple negative subtype. Conclusions: ClassIII β tubulin had a specific predictive value for pathological response of TC in addition of ER, PgR and Ki-67. Sub-grouping is important for treating triple-negative breast cancer.
Screening in the high-risk populations: Stage of breast cancer when detected by combination imaging with MRI and mammogram.
Authors: Carpenter Kendall W. , Merritt Mindy L. , Gromet Matthew , Chambers Karinn Marie , Sarantou Terry , Flippo Teresa , Fisher Julie Gottlieb , White Richard L.
Published: February 2017

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Background: Screening patients at high-risk for the development of breast cancer consists of MRI and mammography. This retrospective review of screening MRIs in patients designated as high-risk for the development of breast cancer--based on family history alone or a calculated lifetime risk of ≥ 20%--seeks to determine the utility of MRI screening in the detection of early-stage breast cancer. The primary outcome evaluated was stage of malignancy detected through screening imaging.  Methods: Results of screening imaging performed between 1/1/08 and 12/31/11 were retrospectively reviewed. Patients who had a personal history of breast cancer were excluded. Remaining screens were categorized based on the following criteria: family history, BRCA mutation or high-risk as calculated by risk assessment tools. Screens with corresponding core biopsies were evaluated for the following: previous imaging obtained, core biopsy pathology and pathologic staging. Results: 118 patients met inclusion criteria and had a subsequent biopsy as a result of screening. Resultant pathology was 75 (64%; 75/118) benign lesions, 19 (16%; 19/118) atypical lesions, and 24 (20%; 24/118) malignant lesions. Of the 24 malignant lesions, 1 (4%; 1/24) were found to be node-positive at the time of surgical staging, and, 23 (96%; 23/24) were node-negative. Conclusions: Four percent (1/24) of patients undergoing high-risk screening had nodal disease at surgical staging, which compares favorably to historical rates of approximately 30% node-positive disease at diagnosis (Krag DN et al., NSABP B-32). Therefore, this study shows that screening high-risk patients can decrease the nodal-positivity rate.
Ten-year outcomes of accelerated partial breast irradiation compared with whole breast irradiation: A matched-pair analysis.
Authors: Wobb Jessica , Wallace Michelle , Shah Chirag , Ye Hong , Jawad Maha Saada , Marvin Kimberly , Grills Inga S. , Chen Peter Y
Published: February 2017

55

Background: Breast conserving therapy (BCT) represents a standard of care in the management of early stage breast cancer; while adjuvant radiation therapy was traditionally delivered using whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) offers an alternative to WBI that shortens the duration of treatment and may improve toxicity profiles and quality of life. The purpose of this analysis is to compare clinical outcomes of patients treated with WBI versus APBI. Methods: A total of 3,009 patients were treated with BCT at single institution between 1980 and 2012 with 2,528 patients receiving WBI and 481 patients receiving APBI (interstitial or balloon-based). A matched-pair analysis was performed with patients matched according to age (+/- 3 years), T stage (Tis vs T1 vs T2), and estrogen receptor (ER) status (+/-). All patients had a minimum of 12 months of follow up. A total of 247 matches were made with clinical outcomes compared using the Kaplan-Meier method. Results: Mean follow-up was 8.1 years for WBI vs. 7.8 years for APBI (p<0.001), a difference of less than 4 months. There were no differences with respect to age (p=0.88), tumor stage (p=1.0), or ER status (p=1.0). Long-term cosmesis was good to excellent in 94% vs. 95% of patients (p=0.78). WBI patients demonstrated a trend for slightly larger tumors (13.0 vs. 11.4 mm, p=0.06). At 10 years, no difference in ipsilateral breast tumor recurrence (4% vs. 4%, p=0.11), regional recurrence (1% vs. 1%, p=0.20), distant metastases (3% vs. 6%, p=0.47), disease free survival (93% vs. 91%, p=0.10), or contralateral breast failure (9% v. 3%, p=0.06) was noted when comparing WBI and APBI. In addition, 10 year cause-specific survival (94% v. 93%, p=0.72) and overall survival (83% vs. 75%, p=0.34) were similar. Conclusions: At 10 years, no differences in locoregional recurrence, distant metastasis or survival were found between patients undergoing whole breast irradiation or accelerated partial breast irradiation using interstitial catheter or balloon-based brachytherapy. These data represent one of the only APBI series with prolonged follow-up and show similar outcomes in a matched group of patients undergoing WBI or APBI.
Dosimetric comparison of 3D-field-in-field technique and inverse planning IMRT for large-breasted patients treated in prone position.
Authors: Kabarriti Rafi , Savacool Michelle K. , Patel Shyamal , Hong Linda , Tome Wolfgang A. , Fox Jana Lauren , Kalnicki Shalom
Published: February 2017

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Background: Whole breast irradiation (WBI) leads to acute and late toxicities, which can be worse with plan dose inhomogeneities. This has been of clinical concern for large-breasted patients, especially with hypofractionation. Two approaches of 3D modulation of the radiation beam profile to optimize dose distribution and improve homogeneity are commonly employed. One is field-in-field forward planning wherein up to 3 or 4 subfields are generated within the initial radiation field. The other is inverse-planning IMRT, which typically utilizes 5 or more segments. In this study, we compare dosimetric parameters of WBI using the field-in-field technique with up to 3 subfields (3D-FiF) compared with inverse planning IMRT in large breasted patients. Methods: 10 large-breasted patients (planning target volume [PTV] >2500cc) treated between 2007-2013 with WBI in the prone position with hypofractionation (42.4 Gy in 16 fractions) were selected. For each, an inverse planning IMRT and a 3D-FiF plan were created for the treated breast. Plans were normalized so that V95% PTV coverage was the same. Dose-volume histograms were evaluated for volumes receiving > 105% (V105) and >107% (V107) of prescribed dose, and maximum dose (Dmax). Results: Median PTV was 3443cc (2675-3875) and median separation distance at the chestwall posterior field edge was 25.9cm (23.7-27.3). IMRT significantly (p<0.005, wilcoxan) reduced the volume receiving V105 and V107. Mean V105 and V107 for IMRT were 124cc (6-266) and 1.3cc (0-11.8), respectively. Mean V105 and V107 for 3D-FIF were 525.6cc (259-765) and 86 (6-171). IMRT also significantly reduced Dmax from a mean of 109.4% to 106.7%. 3D-FiF was able to limit max dose below 110% in 9 of 10 patients. Conclusions: 3D-FiF can achieve a maximum point dose under 110% of prescribed dose with similar target coverage to IMRT for most large breast patients. However, IMRT can significantly reduce the V105 and V107 in these women. Improved dose homogeneity is expected to provide a benefit in terms of acute skin toxicities and late breast fibrosis in such large breasted women receiving WBI with hypofractionation; however further study is needed to prove its true clinical benefit.
Efficacy of HER2-targeted therapy for patients with HER2-positive breast cancer according to hormone receptor status.
Authors: Murata Takeshi , Takahashi Maiko , Hayashida Tetsu , Jinno Hiromitsu , Kitagawa Yuko
Published: February 2017

97

Background: Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive tumors generally cluster within the luminal/HER2 subset; whereas HR-negative/HER2-positive tumors reside in HER2-enriched subset. We investigated whether the efficacy of HER2-targeted therapy for HER2-positive tumors differs by HR status. Methods: Sixty-eight patients with operable breast cancer received trastuzumab plus taxane based therapy before surgery at Keio University Hospital from March 2009 to April 2012. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, and Ki67 were performed by IHC in core needle biopsy samples at baseline. Pathological complete response (pCR) defined as no invasive residuals in breast. All patients with luminal/HER2 tumors received adjuvant endocrine therapy in addition to adjuvant trastuzumab monothereapy. Results: Sixty-eight patients with HER2-positive tumors were divided into 35 (51.5%) patients with luminal/HER2 tumors and 33(48.5%) patients with HER2-enriched tumors, respectively. There were no significant differences in tumor size, clinical nodal status, nuclear grade, and Ki67 status between the two groups. Clinical complete response rate and objective response rate were similar between the two groups. Patients with luminal/HER2 tumors were significantly younger than patients with HER2-enriched tumors (median age (range): 53 (35-78) vs. 61 (31-72), p=0.041). Compared to patients with luminal/HER2 tumors, patients with HER2-enriched tumors had significantly higher pCR rate (28.6% vs. 69.7%, p=0.002). With 24 months median follow-up, no significant differences were observed between the two groups with respect to disease-free survival. Estimated 2-year disease-free survival for luminal/HER2 and HER2-enriched was 94.3% and 97.0%, respectively (p=1.000). Conclusions: HER2-enriched breast cancer showed significantly higher pCR rate to HER2-targeted therapy compared with luminal/HER2 breast cancer. However, there was no significant difference in disease-free survival between the two groups.