bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival and Failure Patterns of High-Grade Gliomas After Three-Dimensional Conformal Radiotherapy
Authors: Chan June L. , Lee Susan W. , Fraass Benedick A. , Normolle Daniel P. , Greenberg Harry S. , Junck Larry R. , Gebarski Stephen S. , Sandler Howard M.
Published: February 2017

PURPOSE: The goal of three-dimensional (3-D) conformal radiation is to increase the dose delivered to tumor while minimizing dose to surrounding normal brain. Previously it has been shown that even escalated doses of 70 to 80 Gy have failure patterns that are predominantly local. This article describes the failure patterns and survival seen with high-grade gliomas given 90 Gy using a 3-D conformal intensity-modulated radiation technique.

PATIENTS AND METHODS: From April 1996 to April 1999, 34 patients with supratentorial high-grade gliomas were treated to 90 Gy. For those that recurred, failure patterns were defined in terms of percentage of recurrent tumor located within the high-dose region. Recurrences with more than 95% of their volume within the high-dose region were considered central; those with 80% to 95%, 20% to 80%, and less than 20% were considered in-field, marginal, and distant, respectively.

RESULTS: The median age was 55 years, and median follow-up was 11.7 months. At time of analysis, 23 (67.6%) of 34 patients had developed radiographic evidence of recurrence. The patterns of failure were 18 (78%) of 23 central, three (13%) of 23 in-field, two (9%) of 23 marginal, and zero (0%) of 23 distant. The median survival was 11.7 months, with 1-year survival of 47.1% and 2-year survival of 12.9%. No significant treatment toxicities were observed.

CONCLUSION: Despite dose escalation to 90 Gy, the predominant failure pattern in high-grade gliomas remains local. This suggests that close margins used in highly conformal treatments do not increase the risk of marginal or distant recurrences. Our results indicate that intensification of local radiotherapy with dose escalation is feasible and deserves further evaluation for high-grade gliomas.
Gemcitabine, Carboplatin, and Paclitaxel for Patients With Carcinoma of Unknown Primary Site: A Minnie Pearl Cancer Research Network Study
Authors: Greco F. Anthony , Burris Howard A. , Litchy Sharlene , Barton John H. , Bradof James E. , Richards Paul , Scullin Daniel C. , Erland Joan B. , Morrissey Lisa H. , Hainsworth John D.
Published: February 2017

PURPOSE: To evaluate the efficacy and toxicity of the novel chemotherapy combination that includes gemcitabine, carboplatin, and paclitaxel in the treatment of patients with carcinoma of unknown primary site.

PATIENTS AND METHODS: One hundred twenty patients were treated with the following regimen, administered every 21 days for a planned four courses: gemcitabine 1,000 mg/m2 intravenously (IV) on days 1 and 8, carboplatin at an estimated area under the concentration-time curve of 5 mg min/mL IV on day 1, and paclitaxel 200 mg/m2 IV on day 1. After four courses, stable and responding patients were given weekly paclitaxel 70 mg/m2 IV for 6 weeks for three 8-week courses. All patients had relatively poor prognostic features. Sixty-three patients had well-differentiated adenocarcinoma, 56 patients had poorly differentiated carcinoma, and 104 patients had performance status of 0 or 1.

RESULTS: Twenty-eight (25%) of 113 assessable patients (95% confidence interval, 22% to 30%) had major objective responses to treatment. Response rates were similar in the two major histologic types. Response rate did not seem to be improved by continued therapy with weekly paclitaxel. The median progression-free survival time was 6 months. Median survival for the entire group was 9 months, and the actuarial survival at 1 and 2 years was 42% and 23%, respectively.

CONCLUSION: Combination chemotherapy with gemcitabine, carboplatin, and paclitaxel followed by weekly paclitaxel is an active and tolerable treatment for patients with carcinoma of unknown primary site. The survival seen in this poor-prognosis group of patients in this multicenter community-based trial is notable and similar to other taxane-based regimens for these patients. Study of additional combinations or sequences of newer drugs, as well as the exploration of targeted biologic agents for patients with an identified target in their tumors, is warranted.
Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies
Authors: Heinrich Michael C. , Blanke Charles D. , Druker Brian J. , Corless Christopher L.
Published: February 2017

PURPOSE: Activation of the KIT tyrosine kinase by somatic mutation has been documented in a number of human malignancies, including gastrointestinal stromal tumor (GIST), seminoma, acute myelogenous leukemia (AML), and mastocytosis. In addition, paracrine or autocrine activation of this kinase has been postulated in numerous other malignancies, including small-cell lung cancer and ovarian cancer. In this review, we discuss the rationale for and development of KIT tyrosine kinase inhibitors for the treatment of human malignancies.

MATERIALS AND METHODS: Studies were identified through a MEDLINE search, review of bibliographies of relevant articles, and review of abstracts from national meetings.

RESULTS: Four tyrosine kinase inhibitors that have activity against KIT are currently being used in clinical trials, and one, STI571, has recently been approved by the United States Food and Drug Administration for treating patients with chronic myelogenous leukemia. The role of KIT inhibitors in treating KIT-positive malignancies is reviewed.

CONCLUSION: Targeted therapy to inhibit the kinase activity of KIT is a rational approach to the treatment of KIT-positive malignancies. Two key factors are the potency of a given inhibitor and the relative contribution of KIT activation to the growth of the tumor. Given our current understanding of KIT activity in human malignancy, the best candidate diseases for treatment with KIT inhibitors are GIST, mastocytosis, seminoma and possibly some cases of AML. Additionally, KIT inhibitors may play an adjunctive role in diseases such as small-cell lung cancer, in which KIT activation is secondary to ligand binding rather than an acquired mutation.
Outcome in adolescent and young adult (AYA) patients compared with younger patients treated for high-risk B-precursor acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group study AALL0232.
Authors: Larsen Eric , Raetz Elizabeth A. , Winick Naomi Joan , Salzer Wanda L. , Nachman James B. , Devidas Meenakshi , Hunger Stephen , Carroll William L.
Published: February 2017

CRA9508

Background: Historically, AYA patients (>16yrs of age) with HR-ALL have an inferior outcome compared to HR-ALL patients 1-15 yrs old, due to increased rates of both relapse and toxicity. Methods: AALL0232 was a phase III randomized trial for patients 1-30 years of age with newly diagnosed B-precursor HR-ALL that utilized a 2 x 2 factorial design with an augmented intensity Berlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. A total of 2,574 eligible, evaluable, non-Down Syndrome, non-very high risk patients were randomized between January 2004 and January 2011. AYA patients comprised 20% of this group (n=501; 16-21 yrs: 466 and 22-30 yrs: 35). Results: The 5-yr event-free survival (EFS) and overall survival (OS) rates were 68.0% and 79.8% for AYA patients compared to 80.9% and 88.4% for younger patients (p<0.0001). The 5-yr cumulative incidence of relapse was 21.3% for AYA patients and 13.4% for younger patients (p=0.0018), largely due to higher rate of marrow relapse (15.2% vs. 9.0%; p<0.0007) and not CNS relapse (5.2% vs. 3.7%; p=0.5776). In addition, fewer AYA patients achieved remission, defined as <5% marrow blasts at end induction (97.2% vs. 98.8%; p=0.0134). There was no significant difference in induction mortality between AYA and younger patients, 2.4% vs. 1.8% (p=0.36). However post-induction remission deaths were significantly higher in AYA compared with younger patients, 5.5% vs. 2.1% at 5 years (p<0.0001). Conclusions: This is the largest cohort of AYA ALL patients presented to date and confirms high cure rates for AYA patients treated on pediatric ALL trials. AYA HR-ALL patients had lower EFS and OS compared to younger patients, primarily attributable to both higher rates of marrow relapses and remission deaths. Effective strategies to improve the outcome of AYA patients with HR-ALL should be aimed at both furthering leukemia eradication and lowering toxicity of therapy for this patient population.
Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA).
Authors: Parker Chris , Nilsson Sten , Heinrich Daniel , O'Sullivan Joe M. , Fossa Sophie D. , Chodacki Ales , Wiechno Pawel J. , Logue John P. , Seke Mihalj , Widmark Anders , Johannessen Dag Clement , Hoskin Peter , Bottomley David , Coleman Robert Edward , Vogelzang Nicholas J. , O'Bryan-Tear C. Gillies , Garcia-Vargas Jose E. , Shan Minghua , Sartor A. Oliver
Published: February 2017

LBA4512

Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 µm). ALSYMPCA, a phase III double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo plus BSC in CRPC patients (pts) with bone mets. In a planned interim analysis (n = 809), based on 314 events, Ra-223 significantly improved overall survival (OS) vs placebo (median 14.0 mo vs 11.2 mo, respectively; HR = .695; 95% CI, .552-.875; 2-sided p = .00185). Secondary endpoints were met and Ra-223 safety was favorable. An updated analysis was conducted prior to the crossover to further assess the effect of Ra-223 on the primary endpoint (OS), secondary endpoints including skeletal-related events (SREs), and safety. Methods: Eligible pts had confirmed symptomatic CRPC with ≥ 2 bone mets; no known visceral mets; and were post-docetaxel, unfit for docetaxel, or had declined docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wks or matching placebo. An updated descriptive analysis of OS, based on 528 events, was performed including data from all randomized pts prior to implementing crossover to Ra-223 for placebo pts. Results: 921 pts (Ra-223, n = 614; placebo, n = 307) were randomized from 6/2008-2/2011. Ra‑223 significantly improved OS vs placebo (median 14.9 mo vs 11.3 mo, respectively; HR = .695; 95% CI, .581-.832; p = 0.00007), and time to first SRE was significantly prolonged (median 15.6 mo vs 9.8 mo, respectively; HR = 0.658; 95% CI, 0.522-0.830; p = 0.00037). Safety and tolerability of Ra-223 remained favorable, with low myelosuppression (e.g., gr 3/4 neutropenia in 2.2% and 0.7% and gr 3/4 thrombocytopenia in 6.3% and 2% of the Ra-223 and placebo groups, respectively). Conclusions: On updated analysis, the median OS benefit for Ra-223 increased from 2.8 to 3.6 months, with a hazard ratio of 0.695 (i.e., 30.5% reduction in risk of death). Ra-223 is an effective therapy that improves OS and time to first SRE with a highly favorable safety profile, and may provide a new standard of care for CRPC pts with bone mets.
METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM).
Authors: Robert Caroline , Flaherty Keith T. , Hersey Peter , Nathan Paul D. , Garbe Claus , Milhem Mohammed M. , Demidov Lev V. , Hassel Jessica C. , Rutkowski Piotr , Mohr Peter , Dummer Reinhard , Trefzer Uwe , Larkin James M. G. , Utikal Jochen , Casey Michelle , Sherman Laurie Jill , Crist Wendy A. , Wu Frank S. , Patel Kiran , Schadendorf Dirk
Published: February 2017

LBA8509

Background: Dacarbazine (D) and paclitaxel (P) have been used to treat MM pts with limited effect. The MM treatment landscape has recently changed with the approval of vemurafenib and ipilimumab in 2011, but secondary malignancies or other toxicities are of concerns. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. In a PhII trial (NCT01037127), pts with BRAFV600E mutation MM had median PFS of 5.3 mos. This PhIII trial (NCT01245062) was conducted in pts with BRAFV600E/K mutant advanced or MM. Methods: Pts were randomized 2:1 to T (2mg QD) or C (D or P). Pts were stratified by baseline LDH level and prior C; pts in the C arm were allowed to crossover to receive T after confirmation of PD. Primary endpoint was PFS in pts with BRAFV600E mutation-positive MM and no prior brain mets; secondary endpoints were OS, ORR and safety in primary and ITT. PFS and OS were compared using a stratified log-rank test. The study was designed with ≥99% power and one-sided α = 0.025 to detect 57% reduction in the risk of PD or death in pts treated with T vs C. Results: Between Dec 2010 and Jul 2011, 322 pts were randomized to T (n=214) or C (n=108); 273 pts were BRAFV600E mutation-positive with no prior brain mets. HR for primary population for PFS by investigator was 0.44 (95% CI 0.31–0.64; p<0.0001) in favor of T with a median PFS of 4.8 mo vs 1.4 mo with C. PFS benefit in favor of T was observed in ITT; this was confirmed by an independent review. The confirmed ORR was 24% with T and 7% with C. HR for interim OS was 0.53 (95% CI 0.30–0.94; p=0.0181), in favor of T in primary population. OS benefit was consistent in ITT pop despite 51 pts crossover from C to T. The most frequent AEs with T were skin rash, diarrhea, edema, hypertension, fatigue. Known MEKi class effects were observed, e.g. chorioretinopathy (<1%) and decreased ejection fraction (7%). Grade 3 AEs in T arm were hypertenstion (12%) and rash (7%). Conclusions: T is the first in class MEKi associated with a significant improvement of PFS and OS compared to C in pts with BRAFV600E/K mutant MM.
Effects of everolimus (EVE) on disease progression in bone and bone markers (BMs) in patients (pts) with bone metastases (mets).
Authors: Hart Lowell L. , Baselga José , Rugo Hope S. , Noguchi Shinzaburo , Pritchard Kathleen I. , Burris Howard A. , Piccart-Gebhart Martine J. , Eakle Janice F. , Mukai Hirofumi , Iwata Hiroji , El-Hashimy Mona , Rao Shantha , Panneerselvam Ashok , Taran Tanya , Hortobagyi Gabriel N. , Sahmoud Tarek , Lebwohl David Edward , Gnant Michael
Published: February 2017

102

Background: BOLERO-2, a multinational, double-blind, placebo-controlled, phase III study in postmenopausal women with estrogen-receptor–positive breast cancer (BC) refractory to nonsteroidal aromatase inhibitors (NSAIs), showed significant clinical benefits with the addition of EVE to exemestane (EXE) (Baselga J et al. NEJM2011 Epub). As bone resorption is an important factor in BC mets, it is interesting to study bone-related effects of EVE. In preclinical studies, mTOR inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effects of EVE vs placebo (PBO) on BM levels and BC progression in bone in pts with bone mets at baseline. Methods: Eligible pts were treated with EXE (25 mg once daily) and randomized (2:1) to EVE (10 mg once daily) or PBO. Bone turnover markers (BMs) were exploratory endpoints analyzed at 6 and 12 wks after treatment initiation and included bone-specific alkaline phosphatase, amino-terminal propeptide of type I collagen, and C-terminal cross-linking telopeptide of type I collagen. Progressive disease in bone (PDB) was defined as worsening of a preexisting bone lesion or a new bone lesion. Results: Baseline disease characteristics, including bone mets at baseline (n = 370, 76% EVE vs n = 184, 77% PBO), were well balanced between arms (N = 724), and baseline bisphosphonate use was not (44% EVE vs 55% PBO). At 12.5 mo median follow-up, progression-free survival (primary endpoint), overall response rate, and clinical benefit rate (p < 0.0001, all) were significantly higher with EVE (n = 485) vs PBO (n = 239). BM levels at 6 and 12 wks increased vs baseline with PBO but decreased with EVE. The cumulative incidence rate of BC PBD was lower for EVE vs PBO at day 60 (3.03% vs 6.16%, respectively), and this trend was sustained beyond 6 months. Updated results will be presented. All bone-related adverse events reported were grade 1-2 and occurred with similar frequency in EVE (2.9%)- and PBO (3.8%)-treated patients. Conclusions: Exploratory analyses from BOLERO-2 suggest that adding EVE has beneficial effects on bone turnover and BC progression in bone in pts receiving EXE therapy for NSAI-refractory BC.
Phase II randomized trial of toremifene 120 mg compared with exemestane 25 mg after prior nonsteroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive breast cancer.
Authors: Iwase Hirotaka , Yamamoto Yutaka , Ishikawa Takashi , Hozumi Yasuo , Ikeda Masahiko , Iwata Hiroji , Yamashita Hiroko , Toyama Tatsuya , Chishima Takashi , Kimijima Izo , Ibusuki Mutsuko , Saji Shigehira
Published: February 2017

105

Background: The non-steroidal aromatase inhibitors (nsAIs) have been mainly employed as adjuvant therapy or as early recurrent treatment for postmenopausal breast cancer with hormone receptor-positive tumor. When its treatment fails, it is unclear which endocrine therapy including selective estrogen receptor modulator (SERM), steroidal AI (sAI), or fulvestrant is the most appropriate. Methods: Open labeled multicenter randomized comparative trial of high-dose toremifene for nsAI resistant breast cancer compared to exmestane (Hi-FAIR ex; registry number UMIN000001841) was performed from Nov 2008 to Oct 2011. Toremifene 120 mg (TOR120) or exemestane 25mg (EXE) was administered once daily. The primary end point was clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Results: A total of 91 women were randomly assigned to TOR120 (n=46) or EXE (n=45). Two of 46 cases allocated for TOR120 refused this trial before the administration. There was no difference of patients’ characteristics between both groups. In the analysis as of median 16.9 months for an observation period, TOR120 were superior to EXE in CBR (47.5% vs. 26.7%; p=0.046) and in PFS (Hazard ratio; 0.62, 95% CI; 0.38-0.99, p=0.047). There was, however, no statistical differences in ORR (11.6% vs. 2.2%; p=0.065) and in OS (hazard ratio; 0.57, 95% CI; 0.24-1.34, p=0.19). Both treatments were well-tolerated, with no severe adverse events, although 3 of 44 women treated by TOR120 were stopped in a couple of weeks because of nausea and general fatigue which were thought to be early endocrine-related symptoms. Conclusions: Our data suggested that toremifene 120mg, as a following therapy for postmenopausal metastatic breast cancer who have failed non-steroidal AI treatment, could be potentially useful than steroidal AI.
Efficacy and safety of metronomic chemotherapy with all-oral combination of low-dose etoposide/capecitabine in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.
Authors: Wei Yan
Published: February 2017

115

Background: The purpose of this study is to determine the efficacy and safety of metronomic chemotherapy with all-oral combination of low-dose etoposide/capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and/or taxanes. Methods: From June 2008 to April 2012, 22 women with MBC were enrolled and 16 patients were evaluable for toxicity and response. Treatment consisted of capecitabine (1,400 mg/m2 daily, taken in 2 oral doses) on days 1-14 and oral etoposide ( 30 mg/m2 daily ) on days 1-7 . Cycles were repeated every 3 weeks unless disease progression or unacceptable toxicity occurred or patient consent was withdrawn. The primary endpoint was clinical benefit rate (CR + PR + SD≥24 weeks); secondary endpoint was toxicity and time to progression (TTP). Tumor response was evaluated by RECIST criteria, and adverse events were evaluated by NCI-CTC AE v3.0. Results: Sixteen patients were included and received 145 cycles of chemotherapy, with a median of 7 cycles (range, 2-26 cycles). One of the 16 patients had partial response (PR 6.25%), 10 showed stable disease (SD 62.5%) and 5 had progression of disease (PD 31.25%), with a clinical benefit rate of 50% (CR + PR + SD≥24 weeks). Median TTP was 5.0 months (range, 1.5-20 months), and mean TTP was 6.06 months. Adverse effects were mild, and the main adverse effects were leucopenia (13%) and fatigue (13%). All patients are survival till now. Conclusions: An all-oral combination of low-dose etoposide plus capecitabine is a new regimen and has showed effective in treating MBC patients and can be well tolerated. It’s very economic compared with most other schedules today. It is worthy of further study on a large scale, especially in the developing countries.
Targeting of endocrine therapy resistance through combined mTOR and histone deacetylase inhibition.
Authors: Ordentlich Peter , McCulloch William , Flechsig Susanne , Hoffmann Jens
Published: February 2017

130

Background: Primary and acquired resistance to endocrine therapy in advanced breast cancer presents a significant barrier to maximizing the clinical effectiveness of these agents. We recently reported in a randomized, placebo controlled phase II study that entinostat (ENT), a class 1 selective HDAC inhibitor, combined with exemestane extended PFS and OS in postmenopausal women with ER+ positive breast cancer that had progressed on a prior nonsteroidal aromatase inhibitor. Likewise, everolimus (EVE), a mTORi, combined with exemestane or tamoxifen (TAM) also significantly extended PFS in a similar patient population. In order to determine the potential benefit of combining ENT with EVE plus hormone therapy we have piloted a series of xenograft studies in primary human tumor models of TAM sensitivity and resistance. Methods: Athymic nude mice bearing xenografts of tissue derived directly from patient tumors (MaCa4049 – TAM sensitive; MaCa3366/TAM – TAM resistant) were treated with A) vehicle B) 2 mg/kg EVE C) 2 mg/kg EVE + 10 mg/kg TAM D) 15 mg/kg ENT E) 2 mg/kg EVE + 10 mg/kg TAM + 15 mg/kg ENT. Tumor samples taken at the end of the study were cryoconserved for analysis of gene and protein expression and protein phosphorylation. Results: Growth of MaCa4049 tumors was inhibited in all treatment groups relative to vehicle in two independent studies conducted in this tumor model. Groups B, C and D demonstrated a similar level of activity while maximal inhibition was observed in Group E. All treatments were generally well tolerated with weight loss similar in groups C and E. Treatment of MaCa3366/TAM tumors is ongoing with similar levels of tumor growth inhibition in all groups observed relative to vehicle at week 7. Analysis of tumor samples from completed studies will be presented to provide insight into mechanism of action for the enhanced activity observed with the triple combination. Conclusions: Preclinical data demonstrating enhanced activity of entinostat combined with everolimus and hormone therapy provides the rationale for clinical investigation of this novel therapeutic approach to targeting hormone therapy resistance.
Single-institution experience with neoadjuvant chemotherapy for metaplastic breast cancer (MBC).
Authors: Kaminsky Anna
Published: February 2017

140

Background: Metaplastic breast carcinoma (MBC) is a rare subtype that accounts for <1% of all breast carcinomas. MBC is frequently triple-negative and neoadjuvant chemotherapy (NAC) is often used in triple-negative breast cancer (TNBC). The objective of this analysis is to ascertain response rates of MBC to NAC as compared to non-metaplastic TNBC. Methods: We searched the Magee Women’s Cancer Center of UPMC IRB-approved neo-adjuvant treatment database which contains outcome data on 594 patients treated from 2004-2010. 116 patients with triple negative breast cancer (ER /PR negative or ER /PR weakly positive [H score of 10 or less] and HER2 negative or indeterminate [HER2 1+ or 2+ without amplification by FISH]), were identified. Nine of these TNBCs had metaplastic subtype and two groups were analyzed: metaplastic breast carcinoma (MBC) (N= 9) and non-metaplastic breast carcinoma (NMBC) (N = 107). Tumor volume reduction (TVR), pathologic complete response (pCR), recurrence and mortality were compared in both groups. Results: Average follow-up in MBC group was 43 months and no patients were lost to follow-up. Average tumor size on presentation in MBC group was 4.47 cm while in NMBC group it was 3.33 cm. pCR was noted in 0/9 MBC and 43/107 NMBC cases (p = 0.0253). 6/9 patients had mastectomy, 2/9 had breast conserving surgery (BCS) and 1/9 patients did not have a surgery yet. Average TVR was 28% in MBC cases compared to 74% in NMBCs when cases with pCR were included (p = 0.0001) and 56% when cases with pCR were excluded (p = 0.0202). Follow up on 9 MBC cases revealed 1 recurrence and subsequent death (11%). Follow-up on 64 NMBC patients who failed to achieve pCR revealed 22 recurrences (34%) and 18 of them subsequently died (28%). Follow-up on 43 NMBC cases that achieved pCR revealed 3 recurrences (7%) and 1 death (2%). Conclusions: MBC was characterized by larger size at baseline as compared to NMBC. There were no pCR’s seen in MBC, but some MBC did achieve response that allowed for breast conservation. Although the average tumor volume reduction was significantly less in MBC compared to NMBC, the NMBC that failed to achieve pCR fared much worse than MBC who did not achieve pCR. Therefore, the triple-negative paradox is likely not applicable to MBC.
The surgeon’s impact on ER status.
Authors: Skinner Kristin A. , Farkas Rachel Leah , Mccarthy Krisitn , Tang Ping , Hellman Leanne , Fronk Jeanette , Andrus Carl H. , Peacock James L. , Hicks David G.
Published: February 2017

153

Background: Long ischemic times prior to tissue fixation can lower the accuracy of immunohistochemical staining (IHC). The purpose of this study was to identify factors that impact the time to fixation (TTF), and to determine if TTF impacts prognostic factor (PF) patterns and if TTF can be changed with simple interventions. Methods: Surgeries performed between 2008 and June 2011 for which TTF was noted and PF testing was done were reviewed. TTF, patient age and race, surgeon, date and type of surgery, tumor size, nodal status, grade, and status of ER/PR and HER2 by IHC were noted. TTF was dichotomized into > or <60 minutes. In-Services (IS) for pathology and surgical staff were completed. TTF before and after the IS were compared. Associations between TTF and other factors were assessed using standard methods for contingency tables. Predictors of ER status were evaluated by multivariate analysis. Results: Mean TTF was 72 minutes (range 12-445) TTF was significantly associated with surgeon, type of specimen, and ER status (Table). TTF was an independent predictor of ER status by multivariate analysis. TTF was shorter and less variable after IS. Conclusions: TTF varied significantly between surgeons. IS training of the surgeons and OR and pathology staff can decrease TTF. Longer TTF was associated with increased ER negativity, suggesting that longer ischemic time interferes with IHC for ER. If prolonged TTF leads to false negative ER staining, patients may not receive optimal therapies. To minimize this risk, the breast surgeon should take an active role in minimizing the TTF. [Table: see text]
Active targeting nanoparticle for breast cancer diagnosis and treatment.
Authors: Iwakuma Nobutaka , Toh Uhi , Grobmyer Stephen R. , Koura Keiko , Takenaka Miki , Otsuka Hiroko , Takahashi Ryuji , Shirouzu Kazuo
Published: February 2017

163

Background: Breast cancer remains a major ongoing public health problem among women. Nanotechnology is the exciting field focused on man-made materials in the size range of 1-100 nanometers (nm). Nanoparticles (NPs) are on the scale of many cellular-level processes and hence are attractive for targeting breast cancer. Emerging nanotechnologies promise new approaches to early detection and treatment of breast cancer. Our group has reported Gold Speckled Silica NPs (GSS) as multimodal contrast agents for fluorescence, magnetic resonance and photoacoustic tomographic (PAT) imaging. The near infrared (NIR) optical absorption property of these particles makes them potentially useful for therapeutic applications such as thermal ablation of tumors. Fulfilling the promise of nanotechnologies for patients with metastatic breast cancer, necessitates delivery of nanomaterials to sites of breast cancer. Now we have focused on the cancer metabolism, we have recently developed active targeting NPs with surface functionalizing agent such as glucose conjugated NPs. We hypothesize that active targeting NPs is more incorporated into cancer cells compared to normal NPs. Methods: Human breast cancer cells, BT474, were incubated with active targeting NPs or normal NPs (as control). The tumor cell uptake was assessed using flow cytometry and fluorescence microscopy experiments. Results: Uptake of active targeting NPs was significantly higher than uptake of normal NPs. Conclusions: Active targeting NPs can be used as suitable targeting NPs for development of imaging agents for early diagnosis of breast cancer. Evolving bio-nanotechnologies such as active targeting NPs promise to enhance the early detection and non-invasive treatment of breast cancer.
Prediction of preclinical myocardial damage utilizing cardiac biomarkers and ultrasound myocardial tissue characterization by integrated backscatter in patients with breast cancer treated with postoperative adjuvant radiotherapy.
Authors: Zhang Yong
Published: February 2017

169

Background: To evaluate whether cardiac biomarkers, ultrasonic integrated backscatter (IBS) can predict early myocardial damage in breast cancer patients treated with postoperative adjuvant radiotherapy. Methods: Forty-eight left-sided breast cancer patients treated with modified radical mastectomy and non-anthracycline containing chemotherapy regimen were examined. Baseline blood samples were drawn for cardiac markers analysis, including Troponin T (TnT), C-reactive protein (CRP), and brain natriuretic peptide (BNP). Calibrated myocardial IBS (CMIBS, assessed by comparison of the anterior wall (AW), inferior wall (IW), anteroseptum (AS) and posterior wall (PW) with pericardial IBS intensity), cyclic variation of IBS (CVIBS) and conventional echocardiography parameters (LVIDd: the left ventricular internal diameter at end-diastole; IVSTd: the intraventricular septal thickness at end-diastole; PWTd: the posterior wall thickness at end-diastole; LVDs: the left ventricular end-systolic dimension; EF: the left ventricular ejection fraction; FS: the left ventricular fractional shortening. The peak velocity of early (E) and late ventricular filling (A) were also determined for calculating the ratio E/A) were investigated before the initiation of radiotherapy (group A), during (group B, 3 weeks after the initiation, the cumulative dose was about 30Gy) and after radiotherapy (group C, 5 weeks, the cumulative dose was about 50Gy). At each time point, blood was drawn to measure TnT, CRP, and BNP. Results: TnT, CRP, and BNP did not change over time. CMIBS of AW and AS were significantly increased after radiotherapy both during (group B, p<0.05) and at the end of treatment (group C, p<0.01) and meanwhile CVIBS and E/A were decreased significantly throughout the treatment period (group B, p<0.05 for both; group C, p<0.01 for both) compared with the beginning (group A). Conclusions: Myocardial IBS offers a promising approach for early clinical detection and characterization of evolution of cardiomyopathy induced by radiotherapy in breast cancer patients.
Short-term outcomes of immediate breast reconstruction using implant or tissue expander after mastectomy in breast cancer patients.
Authors: Lee Haekyung , Kim Se Won , Kang Tae Ho , Yoon Chan Seok , Ko Seung Sang , Hur Min Hee , Kang Sung Soo , Seul Chul Hwan
Published: February 2017

176

Background: Mastectomy is a life-saving management but can cause significant adverse reactions. So, breast reconstruction is a concern in recovery after mastectomy. We report our experience with immediate breast reconstruction using implant or tissue expander, which confirmed the oncologic safety and high patients’ satisfaction. Methods: This study is a retrospective review of all patients who underwent reconstruction with implant or tissue expander immediately after mastectomy. Seventy-seven patients underwent breast reconstruction at a general hospital breast cancer center from January of 2008 to December of 2010 and 14 patients were excluded because of follow-up loss. Therefore 63 patients were included. To access patient’s satisfaction, questionnaire was sent to all patients. Results: Mean age of the patients is 44.1 years. ( range: 29-64) After median follow-up periods of 22.4 months, there was 1 case of locoregional recurrence, 1 case of distant metastasis and overall breast cancer specific survival was 100%. Overall major complication rate was 11.1% (7 patients), such as nipple areolar complex (NAC) necrosis and implant removal. Among 10 patients who had NAC necrosis, 6 patients improved after observation, and 4 patients performed NAC excision. Three patients were removed their implant due to severe infection, leakage or dissatisfaction. There were 32 cases of total mastectomy, 12 cases of skin sparing mastectomy (SSM), 19 cases of NAC sparing mastectomy (NSM). According to the result of questionnaire, 84.1% was satisfied with generalized operational result, 77.8% with cosmetic result. Among 19 patients who had performed NSM, 89.5% was satisfied with general result, 84.2% with cosmetic result. Conclusions: Immediate breast reconstruction using implant after mastectomy is technically feasible and oncologically safe as well as relatively good patient’s satisfaction. But we need more long-term experience.
Radiation therapy for malignant phyllodes tumors: An analysis of over 3,100 patients from 1998 to 2009.
Authors: Williams Richelle T. , Gnerlich Jennifer Lynn , Yao Katharine , Jaskowiak Nora T. , Kulkarni Swati
Published: February 2017

183

Background: Malignant phyllodes tumors of the breast are uncommon. Currently, there are no standard treatment guidelines for adjuvant therapy. We hypothesized that there has been a trend towards increased use of radiation despite its uncertain effect on outcomes. Methods: Using the National Cancer Data Base, treatment trends and predictors of radiation utilization were examined for women with malignant phyllodes from 1998 to 2009. Kaplan-Meier and Cox regression were used to determine the effect of radiation on local recurrence (LR), disease-free survival (DFS), and overall survival (OS). Results: Of 3,153 patients, 57.4% underwent lumpectomy and 42.6% underwent mastectomy. Overall, 14.2% received radiation, with utilization doubling over the study period (9.2% in 1998 vs. 19.8% in 2009, p<0.001). Women were significantly more likely to receive radiation if they were diagnosed later in the study (OR 2.25, 95% CI 1.26-4.03), were age 50-59 (OR 1.64, 95% CI 1.13-2.39), had tumors >10cm (OR 2.28, 95% CI 1.55-3.35), or had nodes removed (OR 2.04, 95% CI 1.56-2.69). Race/ethnicity, socioeconomic factors, hospital characteristics, type of surgery, and margin status were not independent predictors of radiation. Of 1,758 patients with known recurrence status, overall recurrence was 13.8% and LR was 5.9%. With 50 months median follow-up and controlling for potential confounders, radiation reduced LR (aHR 0.41, 95% CI 0.18-0.92) but had no impact on DFS or OS. Conclusions: Use of adjuvant radiation for malignant phyllodes doubled from 1998 to 2009. Tumor factors and time were the main determinants of utilization. Radiation decreased LR but had no effect on DFS or OS.
Extent of lymph node involvement in breast cancer patients with sentinel lymph node metastasis.
Authors: Murata Takeshi , Takahashi Maiko , Hayashida Tetsu , Hirose Shigemichi , Jinno Hiromitsu , Mukai Makio , Kitagawa Yuko
Published: February 2017

199

Background: Axillary lymph node dissection (ALND) is a standard procedure in patients with positive sentinel lymph node (SLN). However, the appropriate level of ALND remains to be elucidated. The aim of this study is to determine the extent of lymph node involvement and predictors to assess non-SLN status in patients with metastatic SLNs. Methods: A prospective database of 235 breast cancer patients with metastases in SLNs who underwent ALND at Keio University Hospital from January 2001 to December 2011 was reviewed. Results: The median age of the patients was 54 years (range 28-86 years) and the mean tumor size was 2.08±0.74 cm. The mean total number of sentinel, level I, and level II lymph nodes removed was 2.72, 18.2, and 2.47, respectively. Other tumor factors include 66.5 % lymphatic invasion positive, 23.7% being nuclear grade 3, 89.4% estrogen receptor positive, and 83.2% progesterone receptor positive. Among 235 patients with SLN involvement, non-SLN metastases were identified in 72 (30.7%) patients and 13 (5.5%) patients had metastases at level II nodes.A univariate analysis showed a significant correlation between non-SLN involvement and number of tumor-involved SLNs. The mean number of tumor-involved SLNs in patients with positive non-SLNs was 1.86 compared with 1.33 in patients with negative non-SLNs (p=0.001). Patients with 2 or more positive SLNs showed a significantly higher rate of non-SLN metastases compared with patients with 1 positive SLNs (47.4% (37/78) vs. 22.3% (35/157), p<0.001).The mean number of tumor-involved SLNs in patients with positive lymph nodes in level II was 2.08 compared with 1.46 in patients with negative lymph nodes in level II (p=0.016). Patients with 2 or more positive SLNs showed a significantly higher rate of metastases at level II nodes compared with patients with 1 positive SLNs (10.3% (8/78) vs. 3.2% (5/157), p=0.0026). Conclusions: Among 235 patients with SLN involvement, the positive rate of non-SLN metastases was 30.7%, whereas that of level II lymph nodes was 5.5%. The number of tumor-involved SLNs was a significant predictor of non-SLN involvement and level II lymph node metastases.
Axillary lymph node coverage of tangent radiotherapy: Comparison of supine versus prone positioning.
Authors: Thompson Gregory M. , Lavigne Ruth F. , Dimascio Mark , Bohorquez Carlos , Lamba Michael A. S.
Published: February 2017

200

Background: Recent randomized evidence has demonstrated low rates of axillary nodal failure in patients with one to two positive lymph nodes who receive local therapy with sentinel lymph node biopsy and simple tangential radiotherapy alone. Decreasing utilization of complete axillary nodal dissections has potential implications for radiotherapy treatment delivery design. We sought to compare the inadvertent coverage of the axillary lymph nodal regions between supine versus prone position for whole breast radiotherapy using simple tangent fields. Methods: Twenty patients with breast cancer who had previously received whole breast radiotherapy with simple tangent fields were randomly selected. Patients were selected such that 10 patients had received treatment in the supine position and 10 patients in the prone position. Axillary lymph node levels I-III were contoured by a single physician according to the RTOG breast contouring atlas. The previously generated radiotherapy plans, each to deliver a prescribed dose between 42.56 and 50Gy, were dosimetrically compared to assess differences in coverage of the nodal volumes. Results: In both positions, dose to each of the axillary nodal regions was low. For level I, the volume receiving 95% of the prescribed dose (V95) was 34.7% for supine positioning and 1.6% for prone positioning. All other analyzed volumes, specifically V25 (71.5% vs 32.6%), V50 (63.3% vs 28.2%), and V75 (57.6% vs 24.1%), were 50% greater for supine compared to prone positioning. Level II coverage was less with V95 of 6% and 0.1% respectively. Similarly V25 (32.8% vs 5.7%), V50 (25.7% vs 3.8%), and V75 (20.3% vs 2.1%) were less compared to level one and greater in the supine position. Level III coverage was less than 10% for both positions at all measured volumes of V95, V75, V50, and V25. Conclusions: Delivery of radiotherapy using simple tangents inadequately covers all axillary nodal levels. Coverage is greater in the supine position with very little inadvertent coverage in the prone position. The risk of nodal recurrence should be carefully considered when deciding to use a simple tangential field design. Additional factors such as dose to the lung and heart should also be considered for positioning.
Feasibility of concurrent weekly paclitaxel and radiotherapy in node-positive breast cancer: An experience from India.
Authors: Kumar Mohan , Subramanian Murali , AG Rajeev , Ponni Arul , S Nirmala , Kilara Nalini , MG Janaki
Published: February 2017

201

Background: Breast cancer patients with positive node and extra nodal spread are at a higher risk for distant metastases and they require immediate adjuvant chemotherapy. Similarly patients after breast conservative surgery or with patholgical T3, T4 disease require adjuvant radiation as early as possible. Taxanes have shown good response in node positive patients and are combined in many adjuvant chemotherapy regimens. Hence the current study was taken to assess the feasibility of concurrent weekly paclitaxel and radiotherapy. Methods: A prospective study was conducted on 22 female breast cancer patients after modified radical mastectomy or breast conservative surgery with pathologically positive node. Chest wall or whole breast radiotherapy was given on Tele Cobalt or Linac for a dose of 50 – 50.4Gy in conventional fractionation. Boost of 16 Gy was given to tumor cavity for those undergone breast conservative surgery. All patients received Inj. paclitaxel 60 mg/m2 once a week for 5 weeks. After completion of RT, paclitaxel dose was increased to 80mg/m2 for remaining 7 cycles. This was followed by anthracycline-based treatment sequentially as per standard adjuvant guidelines. Patients assessed weekly and toxicities graded based on CTC version 03. The minimum follow up was 2 months after completion of chemoradiation. Chi-Square test and Fisher exact test were used to interpret the results with literature. Results: See table. Skin reaction was more frequent and severe of all toxicities (p=0.003). With available literatures on adjuvant radiation alone the grade III and higher skin reactions are 3% but in our study it is 28% because of which 5/22 (22%) patients had interruption of both chemotherapy and radiation. Conclusions: Concurrent chemoradiation with weekly paclitaxel in adjuvant treatment of ca breast is associated with more Skin reactions which may result in significant treatment interruptions. It should be practiced cautiously which requires further randomized control studies to assess the toxicities in detail. [Table: see text]
Single-duct nipple discharge: How concerned should we be?
Authors: Allan Michelle E. , Thomson Simon , Baldota Sanjay Zumberlal
Published: February 2017

58

Background: Nipple discharge has a known association with breast cancer, but determining which cases to identify as being at high risk is a complex and controversial task for the clinician. The current policy at West Hertfordshire Hospitals Trust is to offer microdochectomies to all women who present with unilateral single duct discharge, dominant duct discharge or persistent duct discharge and negative cytology and pre-operative imaging. The aim of this study is to determine if a more discriminative approach might be applied to women who present with nipple discharge. Methods: All patients who underwent a microdochectomy over a 4-year period (2006-2011) were assessed. Patient demographics, characteristics, presenting complaint, pre-operative imaging, and pathology results were analysed. Results: Of the 122 patients analysed in this study, only 7 (5.74%) were diagnosed with malignant carcinoma: 4 patients had DCIS; 3 patients had DCIS and IDC. Of these, 2 had bloodstained nipple discharge. Another two women were diagnosed with papillary carcinoma; only one of them presented with bloodstained nipple discharge, although both had single duct discharge only. 42 cases of mammary duct ectasia (34.43%) and 52 cases of papilloma (42.62%) were found. All women with malignant diagnoses were over the age of 55. Although 47 women (38.52%) presented with a history of blood-stained discharge, only 17 of this cohort (36.17%) had positive cytology – one of whom was diagnosed with multifocal intermediate-grade DCIS. The other 16 women were diagnosed with papillomas, duct ectasia, and benign breast disease. Of those 30 women who presented with a history of bloodstained discharge and had negative cytology, only two were diagnosed with carcinoma (DCIS + IDC and papillary Ca); of those 17 with no recorded bloodstained discharge but positive cytology there were no malignant diagnoses. Conclusions: Microdochectomy performed for nipple discharge results in a low rate of malignancy on excision. Our results from this study correspond with other microdochectomy series. It would appear that a cytological diagnosis is an equivocal discriminator for cancer at best. Further work on a prospective study will help to differentiate patient groups who would most benefit from surgical intervention.
Perceived sexual dysfunction in breast cancer survivors.
Authors: Block Elizabeth Anne , Zomerlei Terri Ann , Keto Jessica , Caughran Jamie
Published: February 2017

67

Background: Sexual dysfunction after breast cancer treatment has been well documented in the literature. However, the degree of dysfunction and how best to address this issue in survivors is less clear. We sought to determine the prevalence of patient perceived sexual dysfunction in breast cancer patients in our patient population. Methods of addressing dysfunction, influence on satisfaction, and interfering factors were indentified. Methods: An IRB-approved survey study of English speaking female breast cancer patients stage 0-III, ages 20 to 80, from 2008-2011 was performed. A 30 question survey containing components related to demographic, breast cancer treatment, perceived impact on sexual function due to treatment, overall satisfaction with intimate relationship, and factors interfering with intimate relationships was used. Results: Of the 407 women meeting inclusion criteria, 103 returned an informed consent, and 83 completed the survey. A total of 47 (64%) of responders felt that treatment had a negative impact on their sexual function. Of those, only 23% discussed the issue with a care provider while 60% desired a physician initiated conversation. A negative perception was associated with decreased satisfaction with intimate relationships (p<0.001). The prevalence of treatment related interfering factors such as fatigue, hot flashes, scars, dysparunia, and breast tenderness were cited most frequently. Of these, only the presence of scars was significantly associated with a perceived negative impact on intimate relationships (p<0.04). Women treated with breast conservation were less likely to perceive a negative impact than mastectomy patients (p=0.036). Conclusions: Patient perceived sexual dysfunction is a documented consequence of breast cancer treatment. Our data demonstrates that patients do not feel this issue is addressed during routine care. However, the majority of patients want this issue discussed with their physicians. Sexual dysfunction is independent of age, time post surgery, and interfering factors making it difficult to identify high risk populations. Therefore, sexual dysfunction should be identified in breast cancer patients during follow-up with interventions made when appropriate.