bluuebunny/crossref_metadata_2025 huggingface dataset:
Time spent in the lymphedema state: Area under the curve.
Authors: Armer J. M. , Stewart B. R. , Madsen R.
Published: February 2017

252

Background: The experience of lymphedema (LE) is variable as related to the pattern of LE emergence, with characteristics related to time since diagnosis, duration of the LE episode, frequency of limb volume change (LVC) events, and overall time spent in the state defined as LE. Recognition of these characteristics, examination of trajectories, and application of the ability to quantify LE state through calculation of Area Under the Curve provide an opportunity to explore new ways to quantify LE occurrence to better examine the impact of LE on survivorship outcomes. Further, through these findings researchers and clinicians will better understand the potential variations in lymphedema experience, including patterns of emergence, duration of each episode, frequency of events, and time spent in the lymphedema state.

Methods: Participants were enrolled following BC diagnosis and followed every 6 months through 60 months. The criterion of 10% LVC (LePCT) by perometry was chosen to demonstrate use of trajectories and utility of calculating Area Under the Curve (AUC). We examined times when a participant met the criterion as a means of following the trajectory of LE and quantified the proportion of (calendar) time that a participant appeared to have LE by looking at the AUC determined by the individual’s graph. As study time differed, rather than look at AUC alone, we looked at the percent of time that a participant met the LE criterion by dividing AUC by total study time.

Results: Over the 60-month time-stamps of data collection points, we examined trajectories or patterns of events where participants met the LE criterion of interest. An individual may have a single LVC “spike” or may have multiple “spikes.” These cases may be acute, transient, or chronic. Further, individuals may experience the LVC early or late in the survivorship trajectory. These variations contribute to varying AUC and percent of the (calendar) time that a participant meets the LE criterion.

Conclusions: These approaches provide an opportunity to further examine the association of LVC with psychosocial and functional outcomes of interest in cancer survivorship. They also provide preliminary data for exploring phenotypic differences in presentation and progression of post-breast cancer lymphedema.
Which benefit from subsequent chemotherapy lines beyond the second for women with metastatic breast cancer? Evidence from a single-center retrospective analysis of survivorship.
Authors: Bernardo G. , Palumbo R. , Bernardo A. , Teragni C. , Sottotetti F. , Tagliaferri B. , Strada M. R.
Published: February 2017

255

Background: Although the true impact of chemotherapy (CT) in metastatic breast cancer (MBC) is still debated, in the routine clinical practice an increasing number of women asking for further treatment after progression receive subsequent CT lines. This study aimed to assess which benefit could be brought by the succession of CT lines in patients treated for MBC and to identify women who benefit from these treatments.

Methods: This retrospective analysis included 980 women treated with CT for MBC at our Institution over a 7-year period (May 1999-July 2006). With overall survival (OS) data updated at December 1, 2008, the median follow-up was 125 months (range 48-192), OS and time to treatment failure (TTF) were calculated according to the Kaplan-Meyer method for each CT line. Cox proportional hazards model was used to identify factors that could influence TTF and OS.

Results: Median OS evaluated from day 1 of each CT line decreased with the line number from 34.8 months (980 patients, 1st line, range 4-208) to 22.6 months (838 patients, 2nd line), 14.6 months (684 patients, 3rd line), 12.4 months (302 patients, 4th line), 9.4 months (88 patients, 5th line), 8.2 months (45 patients, seven or more lines). Median TTF ranged from 9.2 months to 7.8 and 6.4 months for the first, second and third line, respectively, with no significant decrease observed beyond the 3rd line (median 5.2 months, range 4.8-6.2). In univariate analysis factors positively linked to a longer duration of TTF for each CT line were positive hormonal receptor status, absence of liver metastasis, adjuvant CT exposure, response to CT for the metastatic disease; in the multivariate analysis the duration of TTF for each CT line was the only one factor with significant impact on survival benefit for subsequent treatments (p<0.001).

Conclusions: CT beyond the 2nd line may be beneficial in a significant subset of women treated for MBC, with improved TTF and OS. These findings could help physician in planning an appropriate strategy of subsequent schedules for women with symptomatic MBC who responded to their 1st line CT, while non responder patients should be considered for clinical trials.
The use of complementary and alternative medicine (CAM) by Irish patients with breast cancer.
Authors: Graham D. M. , O'Connor N. A. , McCaffrey J. , Carney D. N.
Published: February 2017

259

Background: Worldwide, the use of complementary and alternative medicine (CAM) has greatly increased over the last decade. CAM use has been shown to be higher in cancer patients than among the general population and is known to be prevalent in patients with breast cancer. The aim of this study was to investigate the prevalence of CAM use among Irish breast cancer patients; something which has not previously been examined.

Methods: An anonymous cross-sectional survey was offered to all patients attending for treatment of malignancy or cancer-care follow-up at a single Irish Cancer Centre over an 8-week period. The reasons for CAM use and those factors that increase the likelihood of CAM use were also investigated. A subset analysis of patients with a diagnosis of breast cancer was performed.

Results: A total of 230 questionnaires were distributed. 193 patients responded. Of these, 5 were excluded due to lack of demographic data. Of the 188 surveys available for analysis, 91 respondents (49%) had a diagnosis of breast cancer. Thirty-five breast cancer patients (39%) reported having used CAM. This was not significantly different from other cancer types. Of those patients with breast cancer who used CAM, 11 (12%) commenced CAM use following their cancer diagnosis. Respondents who were under 40 (p=0.005), single (p=0.023) and currently in employment (p=0.001) were more likely to use CAM. The most common reason cited for CAM use was to improve physical well-being (46%) and 78% reported a benefit. No patients reported adverse effects from CAM use. The most commonly used therapies were massage/reflexology (58%), relaxation therapy (61%) and herbal teas (58%). CAM medication therapies were used by 31% CAM users, of whom 32% had not informed their doctor.

Conclusions: CAM use is prevalent among Irish breast cancer patients. Use of CAM is more common in young, single, employed patients, in keeping with similar studies in other countries. A significant proportion use CAM medications, which may potentially interact with prescribed treatment. Of note, almost one third of these patients do not inform their doctor. This underlines the need for physicians to ask about CAM use in all patients being treated for breast cancer.
Relationship between implementation of the American Society of Clinical Oncology/College of American Pathologists guideline recommendations for breast core-needle biopsies and delay in therapy for patients with breast cancer.
Authors: Rosen D. , Quraishi M. A. , Middleton L. P. , Yang W. T. , Sahin A. A.
Published: February 2017

26

Background: Recently the ASCO/CAP suggested new guideline recommendations for immunohistochemical (IHC) testing of biomarkers in breast cancer. An algorithm that relies on accurate, reproducible assay performance was proposed and preanalytical, analytical and postanalytical standards suggested. One such recommendation is to have appropriate internal controls when assessing hormone expression. In this retrospective study we evaluated 242 breast core biopsy specimens to assess the impact of the recently proposed ASCO/CAP guideline recommendations and its possible impact on routine daily practice. In addition, we explore the impact of blindly selecting a random core for potential future studies.

Methods: A total 988 cores from 242 specimens corresponding to 224 patients diagnosed between 2008 and 2009 were examined. Each core was examined for the presence of normal glands, percentage of tumor involvement, biomarker status, and diagnostic adequacy.

Results: Absence of normal glands was found on 61/242 specimens (25%). Of these, expression of ER, PR and HER2 was seen in 44 (72%), 28 (46%), and 21 specimens (35%) respectively. Negative staining for ER, PR and HER2 was observed in 7 specimens (12%). A total of 148 cores (15%) showed absence of tumor and 275 cores (28%) had <25% of tumor in them. 18 cores (2%) were insufficient for diagnosis due to either scant tumor present or crush artifact present.

Conclusions: Although the presence of internal control glands is optimal, its presence may be unnecessary if proper IHC batch run controls are utilized and histologic/IHC concordance is performed. Tumor histology and IHC profile concordance is imperative specially in triple negative cases. The impact on patient health care of an “receptor uninterpretable” biopsy is yet to be determined, but likely would include assessment of the delay in care due to a repeat biopsy with procurement of additional tissue, additional heath care costs, and anxiety to the patient. Adequacy check using frozen section could be done to assess for the presence of tumor during the procedure.
Compliance with consensus recommendations for systemic therapy, breast cancer intrinsic subtype, and clinical outcome.
Authors: Takayama S. , Matsui J. , Ando N.
Published: February 2017

262

Background: Consensus recommendations for breast cancer are come into wide use, and we believe clinical guidelines leads our patients to improved outcome. Recently, gene profiling can be available, and immunohistochemical surrogates for molecular subtyping can provide much of prognostic and predictive factors. We investigated the relationship between compliance with consensus recommendations and clinical outcome of each subtype on the hypothesis that conformity with consensus recommendations is associated with increased survival among all intrinsic subtypes.

Methods: We investigated breast cancer patients operated in our hospital from 2002 to 2004. DCIS, Stage 4 and male breast cancer were excluded. Patients were divided into luminal A (ER+ and/or PgR+, HER2-, low nuclear grade (NG)), luminal B (ER+ and/or PgR+, HER2-, high NG), luminal-HER2 (ER+ and/or PgR+, HER2+), HER2 (ER-, PgR-, HER2+) and triple negative (TN), (ER-, PgR-, HER2-). All patients were divided into compliance group or non-compliance group according to their conformity with consensus recommendations. Kaplan-Meier analysis was used in statistical studies.

Results: 121 breast cancer patients were eligible and investigated in this study. Median follow-up period was 6.7 years. Fifteen relapse cases (12.4%) were identified. Among luminal A patients, compliance group was significantly associated with better recurrence free survival compared with non-compliance group with Kaplan-Meier analysis (p<0.001). In contrast, there was no difference between compliance group and non-compliance group among the other subtypes. Median time to recurrence (4.2 year) in non-compliance group among luminal A was apparently longer than that (1.7 year) in compliance group among the other subtypes.

Conclusions: Compliance group was significantly associated with better clinical outcome compared with non-compliance group among luminal A. This study suggests that cautious follow-up is required against non-compliance patients among luminal A, because time to recurrence of them was longer than that of both compliance and non-compliance subgroups among the other subtypes.
Patient factors influencing choice for mastectomy.
Authors: Hart M. R. , Steely A. M. , James T. A. , McCahill L. E.
Published: February 2017

264

Background: The process of shared decision-making in the surgical management of breast cancer is complex. Many women eligible for breast conservation therapy (BCT) still choose total mastectomy (TM), and little is known about the factors responsible for their decision. We conducted a pilot, qualitative study in order to determine factors influencing the selection of TM over BCT, and to improve our understanding of patient’s concerns and priorities in their decision-making process for breast cancer surgery.

Methods: Data were collected from a four-year, prospective Breast Cancer Surgical Quality Database. Study participants included female patients with invasive carcinoma who, despite being eligible for BCT, elected to undergo TM. Eligibility criteria included women with no contraindications to BCT, tumor size <2cm, and no evidence of extensive microcalcifications. Patients with tumor recurrence, multicentric disease, scleroderma, and lupus were excluded. Patients were contacted by phone and administered a survey designed to elicit the specific factors affecting their decision to undergo TM.

Results: Out of 670 patients treated for IDC/ILC between 2003 and 2007, 12 met eligibility criteria and were subsequently interviewed. 10 patients identified fear of recurrence as the prevailing factor in their decision to undergo TM, and 5 patients identified availability of breast reconstruction as a moderate to strong influence in their decision to undergo TM. Time away from work and transportation during radiation therapy had minimal or no influence.

Conclusions: Our results indicate that patients with small, invasive breast cancers who chose TM for their surgical treatment, despite being eligible for BCT, were primarily influenced by fear of recurrence. These decision factors persisted despite treatment at a multidisciplinary center, where patients are informed of equivalent survival and minimal difference in recurrence with appropriate BCT. These results highlight the need for further assessment of patient education and comprehension, as well as greater awareness of emotional factors which may influence a patient’s decision regarding the surgical management of her breast cancer.
Results by treatment modalities in multifocal/multicentric breast cancer: Retrospective analysis of 162 patients.
Authors: Kadioglu H. , Kayahan M. , Ersoy Y. E. , Memmi N. , Bozkurt S. , Cipe G. , Muslumanoglu M.
Published: February 2017

266

Background: The prognostic value of multifocal, multicentric breast cancer is still not well known. Although some studies have suggested that it is associated with a worst prognosis some have not suggest. We evaluated the effect of treatment modalities on overall survival and disease-free survival in breast cancer.

Methods: One hundred and sixty two women with multifocal multicentric breast cancer diagnosed at our oncology center between January 2004 and December 2010 were retrospectively evaluated. Multifocality was defined as the presence of 2 or more foci of the tumor clearly separated in the same breast. Multicentricity was defined as the presence of 2 or more foci at different quadrants. Patients received neoadjuvant chemotherapy were excluded.

Results: Median age of 162 women was 48 y ± 13,63 y. Eighty two of 162 patients were treated with breast-conserving surgery and 80 were treated with mastectomy. Radiotherapy was added to adjuvant therapy to patients with 4 or more positive axillary nodes and/or treated with breast conserving surgery. Three (1.8%) patients were excluded because of bilateral cancer and 1 (0.6%) was excluded because of Tx tumor. Eleven of 162 (6.7%) patients were not seen after surgery so data about adjuvant treatment was not known. Fifty of 147 patients were stage III, 68 were stage II and 30 were stage I. 27 (17.2%) patients received anthracycline based chemotherapy, 30 (20.3%) patients received hormonotherapy and 91 (56.1%) patients received taxane based chemotherapy. Trastuzumab added to the treatment at all patients, if HER2 neu-positive. Median follow up was 41 ± 4.1 (72-9 months) months. 30 systemic diseases at 24 patients were seen on follow up. 18 patients were in taxane group, 4 patients were in anthracycline group, 2 patients were in hormonotheraphy group. Nine patients were died in taxane group, 1 died in anthracycline group and 1 died in hormonotherapy group.

Conclusions: Our retrospective analysis showed worst prognosis at taxane group but; patients with positive lymph nodes and perinodal invasion gets taxane based treatments. This retrospective analysis showed that systemic recurrence and survival in multifocal breast cancer are similar with unifocal disease.
Effect of oral cyclophosphamide use on pathologic complete response rate in the neoadjuvant treatment of breast cancer.
Authors: Luque M. , Garcia-Teijido P. , Fernandez Y. , Sampedro T. , Reguero V.
Published: February 2017

276

Background: Continuous exposure to cyclophosphamide (C) can result in selective cytotoxicity for endothelial cells, followed by antiangiogenic effects on tumor cells. In this study we analyzed the pathological complete response (pCR) rate in a cohort of patients (p) diagnosed with locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy (CT) based on anthracyclines and taxanes, depending on the route of administration of C (intravenous (IV) and oral arms).

Methods: We retrospectively studied a consecutive series of p. with LABC treated with neoadjuvant CT in 2 hospitals in Asturias. The regimens used were CE100F, AC (regimens with IV C) or oral CAF (C 100mg/m2/day orally x 14 days, doxorubicin 30 mg/m2 day 1 and 8 and 5-FU 500 mg/m2 days 1 and 8 every 28 days) x 4 cycles. The anthracycline regimen was followed by weekly paclitaxel or docetaxel every 3 weeks. If HER2 overexpression, trastuzumab was given in combination with the taxane.

Results: We identified 105 p., 65 of them treated with oral C and 40 with IV C (CEF 3 patients and AC 37 patients). The median age was slightly higher in the p. treated with C IV (52.2 vs. 47.7, p = 0.022), which also received a higher number of cycles (7.1 vs. 6.7, p = 0.025), although there were no significant differences in the anthracycline dose intensity (93% vs 89%, p = 0.093). There were no significant differences in tumor size, lymph node involvement, grade, estrogen receptor (ER) or HER2. The rate of pCR was significantly higher in p. receiving oral C (33.8% vs 10%, p = 0.004). Grade 3, negative estrogen receptors and HER2 were also significantly associated with a higher rate of pCR. On multivariate analysis only oral C was an independent factor associated with pCR. With a median follow up of 27.3 months (95% CI 24 to 30.6), there have been 10 recurrences (15.4%) in the continuous arm and 9 (22.5%) in the standard arm, without significant differences in disease free survival.

Conclusions: Our results suggest that the pCR rate can be higher using oral C in the neoadjuvant treatment of LABC based on anthracyclines and taxanes. This hypothesis should be confirmed in a randomized and prospective study.
Pathologic response rate (pCR) and near-pathologic response rate (near-pCR) with docetaxel-carboplatin (TCarb) in early triple-negative breast cancer.
Authors: Kern P. , Kolberg H. C. , Kalisch A. , Liedtke C. , Otterbach F. , Kimmig R. , Kurbacher C. M.
Published: February 2017

277

Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis unless a pathological complete response is achieved (Liedtke C et al. 2008: J Clin Oncol 26:1275-1281) or almost achieved (Symmans WF. 2007: J Clin Oncol 25:4414-4422). Sensitivity to platin compounds has been demonstrated in BRCA1-positive settings (Byrski T et al. 2010: J Clin Oncol 20:28:375-9; Silver DP. 2010: J Clin Oncol 28:1145-1153) with only limited numbers of patients (Byrski T et al. 2010: J Clin Oncol 20:28:375-9) or in sporadic breast cancer with heterogeneous cohorts (Sikov WM et al 2009: J Clin Oncol 27:4693-4700; Chang HR et al. 2010: Cancer 15; 116:4227-4237).

Methods: This pivotal trial was to assess the efficacy of platinum and taxane-based combination therapy without the use of anthracyclines. 27 patients with primary TNBC (majority of them cT2, two cT3 and one cT4a) had to be unsuitable for standard anthracycline-based chemotherapy. They received 6 cycles, respectively in two cases only 5 cycles, of carboplatin AUC 6 and docetaxel 75 mg/m2 q3w. The primary endpoint was the pCR-rate, secondary endpoint toxicity.

Results: 20 out of 27 (74%) patients had pathological complete response (52%) or near-complete response (22%)—ypT1mic and ypT1a—both being associated with a good prognosis. Seven remaining patients had still good partial response, leaving only low residual cancer burden, which was defined as ypT1. Treatment was well-tolerated: grade III and IV toxicities were neutropenia, thrombopenia, oedema, nausea, joint pain, nail changes, fatigue, hypertension, and alopecia.

Conclusions: These results show a high efficacy of carboplatin AUC6 and docetaxel 75 mg/m2 q3w and good feasibility as primary chemotherapy for TNBC with a pCR- and near-pCR-rate of 74% and total response rate of 100%. The incorporation of anthracyclines and parp-inhibitors into further trial designs could enhance the efficacy of these compounds. The omission of exposure to anthracyclines in patients with considerable heart disease risks seems to be feasible with a good pCR-rate, the latter being a surrogate-marker for long-term survival.
Chemotherapy-induced amennorrhea: Predictive markers of response to neoadjuvant chemotherapy in breast cancer.
Authors: Ahn S. K. , Moon H. , Ko E. , Kim J. s. , You J. M. , Shin H. , Han W. , Noh D.
Published: February 2017

281

Background: There is controversy about the benefit of chemotherapy-induced amenorrhea (CIA) in breast cancer. We investigated significance of CIA after neoadjuvant chemotherapy for predicting response to neoadjuvant chemotherapy in breast cancer patients.

Methods: We reviewed the records of 198 premenopausal patients with breast cancer treated with neoadjuvant chemotherapy between January 2005 and December 2010. Chemotherapy-induced amenorrhea (CIA) was defined as serum FSH level ≥40 IU/L after completion of all scheduled neoadjuvant chemotherapy and prior to definitive surgery.

Results: Among 198 breast cancer patients, 132 pts (66.7%) developed CIA after neoadjuvant chemotherapy. 156 pts (78%) underwent DA chemotherapy. The age of CIA patients was older than non-CIA patients (41.55±5.55 vs. 38.27± 6.86 years, p=0.001). The incidence of CIA after neoadjuvant chemotherapy was significantly higher in responder group (responder vs. nonresponder: 87 pts (74.4%) vs. 45 pts (55.6%); p=0.006). Additionally, FSH level after all scheduled neoadjuvant chemotherapy was significantly higher in responder group (FSH 56.41±32.41 mIU/ml vs. 45.76±30.31 mIU/ml; p=0.021). In univariate analysis, CIA (p=0.006) and total number of chemotherapy cycle regardless of chemotherapy regimen (p=0.04) were significantly predictive of tumor response. CIA was only significant predictive factor for tumor response after neoadjuvant chemotherapy on multivariate analysis (p=0.012).

Conclusions: CIA is independent predictive markers of response to neoadjuvant chemotherapy in locally advanced breast cancer.
Mortality reduction in the Swedish mammography screening program.
Authors: Zahl P. H. , Mæhlen J.
Published: February 2017

29

Background: The introduction of a nationwide mammography screening program in Sweden in 1986 was associated with a 50% persistent increase of breast cancer incidence (including carcinoma in situ). Whether screening has been instrumental in a recent decline in the breast cancer mortality remains an open question.

Methods: We compared the 18 years breast cancer mortality for two groups of women; those diagnosed in the first 6 years of the screening program and those diagnosed during a 6 year period that included the last 4 years before screening started and the first 2 years of the screening program. The test group (n + 328,927) included women aged 40 to 69 at the first invitation to screening. On average the women in the age-matched control group (n + 317,404) were born 4 years earlier then the women in the test group. The numbers of incident invasive breast cancers in each county were obtained from the Swedish Cancer Registry (in-situ cancers were excluded) and the corresponding breast cancer deaths were obtained from the Swedish Causes of Death Registry.

Results: After 18 years follow up, the mortality reduction was 14% in the test group. However, most of this difference (10%) occurred in the first five years after diagnosis reflecting improved medical treatment of breast cancer. Most of the 14% difference also disappeared if we adjusting for period effects.

Conclusions: About 83% of women in the test group were also included in the control group making the two groups almost identical with respect to risk variables. By screening the control group at the end of a 6-year period, the results are adjusted for differences due to lead-time bias and by studying mortality instead of survival overdiagnosis (length time bias) is also adjusted for. We conclude that organized mammography screening is not an important cause for the reduction in the breast cancer mortality in Sweden.
Anticancer efficacy of natural withanolides in triple-negative breast cancer through down regulation of BRCA1, cell-cycle arrest, and induction of apoptosis.
Authors: Zhang X. , Samadi A. K. , Mukerji R. , Timmermann B. N. , Cohen M. S.
Published: February 2017

291

Background: Triple negative breast cancer is often chemoresistant creating the need for novel improved drugs for this disease. Naturally derived withanolides such as withaferin A (WA) have shown potent preclinical efficacy in breast cancers. The purpose of this study is to better define the anticancer activity of WA and novel analogs(X001 and X003) containing a 19-OH substitution, in triple negative MDA-MB-231cells where BRCA1 is important for cell survival.

Methods: Cells were treated with increasing doses of WA, X001, or X003 for 24 h. MTS and trypan blue exclusion assays were used to examine cell proliferation and viability. Cell cycle was examined using propidium iodide (PI) staining on flow cytometry (FC). Annexin-V/PI co-staining on FC was used to detect apoptosis. Western analysis was used to evaluate BRCA1 protein levels as well as to confirm apoptosis by PARP cleavage and caspase-3 activation.

Results: X003, WA, and X001 inhibited MDA-MB-231 cell viability (IC50=125, 500 and 1300nM respectively). IC50 level of WA induced G2/M phase cell cycle arrest while 2.5μM also induced apoptosis at 24 h as well as a significant decrease in both total and phospho-Akt protein levels. In addition, WA decreased BRCA1, heat shock factor 1, and mutant p53 protein levels in a dose-dependent manner. 2.5 μM of WA decreased BRCA1 protein levels by 75% compared to controls at 24 h (p<0.01) while its natural analogs X003 and X001 induced apoptosis associated with BRCA1 down-regulation at 200nM (1.5xIC50) and 6.5μM (5xIC50) and a G2/M cell cycle arrest at only 50nM (50%IC50) and 2μM (1.5xIC50) respectively after 24 hours.

Conclusions: Natural withanolides such as WA and its potent analog X003 demonstrate anticancer effects on triple negative breast cancer cells through cell cycle arrest, apoptosis and down-regulation of BRCA1 protein expression. Targeting BRCA1 in triple negative breast cancer with natural withanolides represents a novel approach for future translational studies in this difficult disease.
Phase II trial of RAD001 plus carboplatin in patients with triple-negative metastatic breast cancer.
Authors: Singh J. C. , Stein S. , Volm M. , Smith J. A. , Novik Y. , Speyer J. L. , Adams S. , Meyers M. I. , Muggia F. , Schneider R. , Formenti S. , Davis S. , Choi H. , Tiersten A.
Published: February 2017

293

Background: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer.

Methods: The primary objective of the study is to determine clinical benefit (complete remission; CR, partial remission; PR and stable disease; SD) and the toxicity of this combination in women with triple negative metastatic breast cancer who had received 0-3 prior chemotherapy regimens for metastatic disease. Prior carboplatin was allowed. Women with treated brain metastasis were eligible. Secondary objectives were to determine progression free survival. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. 5 mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a surprising amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg).

Results: Eleven patients of a planned 25 have been recruited thus far. Median age is 62. Median number of prior regimens is 1. Of the 6 patients assessable for response at this time, four have SD and two have had a PR. 1 SD was achieved in a patient progressing on prior carboplatin at study entry. Five of 7 patients assessable for toxicity had grade 3 or 4 thrombocytopenia and 2 patients had grade 3 neutropenia. All patients have had treatment held and/or dose reductions secondary to hematological toxicity. There have been no non-hematological grade 3 or 4 toxicities.

Conclusions: Clinical benefit was observed in all 6 evaluable patients. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing.
Cost-effectiveness of zoledronic acid (ZOL) versus denosumab (Dmab) in prevention of skeletal-related events (SREs) in metastatic breast cancer (mBC).
Authors: Carter J. A. , Snedecor S. J. , Kaura S. , Botteman M.
Published: February 2017

294

Background: Dmab has been approved in the US for prevention of SREs in mBC on the basis of the results of a phase III trial comparing Dmab vs. ZOL in mBC. In this trial, overall survival, disease progression, and serious adverse events (SAEs) were similar across treatments. The cost of a Dmab injection ($1650) is nearly 2x that of ZOLs ($887). This analysis assessed the cost effectiveness of Dmab vs. ZOL in mBC from a US managed care perspective.

Methods: A literature-based Markov model was developed to estimate the survival, quality-adjusted life-years (QALYs), number and costs of SREs, and drug and administration (Dmab=$32.46; ZOL=$153.86) costs for patients (pts) receiving Dmab or ZOL. Inputs were selected to reproduce the phase III trial outcomes up to 28 months. QALYs were estimated by assigning utilities to health states (prior to SRE; SRE; post-SRE, and death). SRE-related costs and utilities were obtained from the literature. Per-event SRE costs ranged from $4,039 (vertebral fracture) to $20,734 (bone surgery). In sensitivity analysis, SAEs were included ($15,441/pt with a SAE). Future outcomes were discounted at 3%/year.

Results: Dmab resulted in fewer SREs, more QALYs, and lower SRE-related costs, but higher drug-related and total costs vs. ZOL, resulting in an incremental cost of $6,884/pt (TABLE). The cost per QALY gained was $644,000 when excluding SAEs ($613,000/QALY when including SAEs).

Conclusions: Dmab is predicted to result in an incremental cost/QALY gained >$600,000. This high cost/QALY is due to the higher drug acquisition cost of Dmab, combined with the limited prevention of SREs and lack of overall survival/disease progression benefits vs. ZOL. The cost/QALY of Dmab is far higher than what is considered to be good value for a medical intervention ($50,000 to $100,000/QALY), thus raising questions regarding Dmab's value in mBC.

[Table: see text]
A phase II open-label trial to evaluate the efficacy and toxicity of erlotinib in women with metastatic, hormone receptor-negative, and HER2-negative breast cancer.
Authors: Rao R. D. , Siziopikou K. P. , Cobleigh M. A.
Published: February 2017

296

Background: There is limited success with current therapies for triple negative (TN) breast cancer. Epidermal growth factor receptor (EGFR) is a therapeutic target in solid tumors. Overexpression of EGFR has been linked to an aggressive breast tumor phenotype with a poor prognosis. Previous work at RUSH showed that 64% of 66 TN tumors were EGFR positive (Siziopikou SABCS 2004). To date, the use of EGFR tyrosine kinase inhibitors (TKIs) in metastatic breast cancer (MBC) has been disappointing. These trials enrolled refractory patients and did not select for EGFR expression. We hypothesized that if selected for EGFR expression, there may be a cohort of TN MBC patients who benefit from an EGFR TKI. This is a phase II study of erlotinib in TN-EGFR-positive MBC.

Methods: Eligible patients had TN-EGFR-positive MBC. EGFR positivity was defined as staining in >10% of tumor cells by IHC (Dako). Patients required measurable disease, prior treatment with anthracycline and taxane (adjuvant or metastatic setting) and ≤1 prior chemotherapy for MBC. Patients received erlotinib 150mg daily. Primary endpoint was progression-free survival (PFS). Initially, 18 patients were to be accrued. If ≥ 3 patients were progression-free at 4 months, accrual would continue to 43.

Results: The study was terminated prematurely due to poor accrual. In total, 11 patients enrolled, 10 were treated. Mean age 56.7y, 18% African-American. Four patients had prior chemotherapy for MBC. Most patients progressed rapidly, median PFS was 29 days (95% CI 25.90 – 32.10). However, 2 patients had stable disease for 225 and 476 days. Treatment was well-tolerated. Toxicities in the 2 patients with stable disease included grade 2 rash, grade 1 diarrhea, grade 1 nausea, grade 2 weight loss and grade 1 diarrhea.

Conclusions: Although most patients progressed rapidly, 2/10 patients had prolonged stable disease. This suggests there may be a subset of TN, EGFR positive MBC for whom EGFR-directed therapy may be suitable or that the natural history of their disease was indolent. Future studies to determine molecular and clinical profiles of patients likely to benefit from EGFR-TKI therapy in this population are warranted.
Pathologic characteristics of breast cancer with special emphasis on prevalence of triple-negative breast cancer from Kenya: A 4-year experience.
Authors: Sayed S. , Moloo Z. , Mukono S. , Wasike R. , Chauhan R. R. , Ndonga A. , Trinkaus M. E. , Rahim Y. , Wedad H. , Saleh M. N.
Published: February 2017

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Background: Previous sub classification of breast cancer in Kenya has been fraught by small sample size, non uniform staining methodology and lack of independent review. Triple Negative Breast Cancer (TNBC) is a “special interest” cancer since it represents a significant proportion of breast cancer patients and is associated with a poorer prognosis. We aimed to determine the estrogen receptor (ER), progesterone receptor (PR) and Her2/neu receptor characteristics of breast cancers and the prevalence of TNBC diagnosed at Aga Khan University Hospital, Nairobi (AKUHN) between 2007 to date.

Methods: Slides and blocks of archived invasive breast cancers diagnosed at AKUHN were identified, retrieved and reviewed by two independent pathologists. Histological type, grade and pathological stage were documented. Representative sections from available blocks were stained for ER, PR, Her2 with appropriate internal controls. Scores for ER/PR were interpreted based on the ALLRED system, Her2 /neu scoring followed CAP guidelines. The initial 111 cases were validated and confirmed at Sunnybrook Health Sciences Centre, Toronto.

Results: 456 cases of invasive breast cancers were diagnosed at AKUHN during the study period. 91% of cases were invasive ductal carcinomas (NOS).The rest were special types. 37% of the tumors were grade 3 and 63% were grade 2. Blocks for 318 of 456 cases were available for receptor analysis. 54% were ER and/or PR positive, with 52% of these in women < 50 yrs. 86% of the ER and/or PR positive tumors were grade 2. Only 12% were Her2/neu positive. Of the 318 cases studied, 111 (32%) were identified as TNBC. Median age was 53 yrs. 88% were grade 3.

Conclusions: Invasive ductal carcinoma (NOS) was the most common breast cancer in our study. Nearly half of our cases were ER and/or PR positive and a third were TNBC. Both occurred predominantly in women less than 50 yrs. This represents the largest validated pathologic sub classification of breast cancer from a tertiary academic hospital in Kenya. Expansion of this study to encompass all breast cancers diagnosed in Kenya is underway.
Prognostic role of triple-negative subtype in breast cancer patients with brain metastases.
Authors: Mathew A. , Rosenzweig M. Q. , Brufsky A.
Published: February 2017

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Background: Metastatic breast cancer (MBC) patients with brain metastases (BM) have a poorer prognosis compared to patients with metastases to sites such as bone or other visceral organs. The role of breast cancer subtypes such as triple negative (TN) status and its relationship with other known prognostic factors have not been well delineated in the context of metastatic disease to the brain. We conducted a retrospective single institution cohort study of MBC patients with BM to evaluate the association between TN subtype and overall survival from the diagnosis of BM.

Methods: Baseline demographic and tumor specific data including ER, PR and HER2 status were collected on newly diagnosed MBC patients between January 1998 and December 2009. Overall survival was determined from the date of diagnosis of BM. Survival analyses were performed using the Kaplan-Meier method and Cox proportional-hazards model.

Results: Data were available on 186 MBC patients with BM, of whom 156 died during a median follow-up of 10.2 months from the diagnosis of BM; median age was 47.9 years. 91% of patients were Caucasian; 25.3% had triple negative disease. Median survival from the period of diagnosis of BM in patients with triple negative disease was 7 months (Interquartile range, IQR: 3–13) as compared to 11 months (IQR: 5–22) in patients who were HER2-positive or ER/PR-positive. Multivariate analysis found a higher risk of death after BM for TN disease subtype, with a hazard ratio for death of 2.89 (95% confidence interval: 1.89–4.44; p<0.001), when adjusted for variables such as age and stage at initial diagnosis of breast cancer, race, the number of metastatic sites, and the use of metastatic chemotherapy. The administration of metastatic chemotherapy had a significant survival benefit in the analyses, with a hazard ratio for death of 0.52 (95% CI: 0.27–0.99; p=0.048).

Conclusions: This retrospective cohort study in MBC patients with BM provides evidence for a greater risk of death in those with TN disease as compared to HER2-positive or ER/PR-positive subtypes even after adjusting for other prognostic factors.
Long-term outcome of DCIS patients: p53 as a biomarker of ipsilateral recurrence.
Authors: Hieken T. J. , Krishnamurthy V. , Farolan M. , Velasco J. M.
Published: February 2017

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Background: Ductal carcinoma in situ (DCIS) is a heterogeneous and potentially curable disease with a long natural history. DCIS represents 21% of breast cancers diagnosed in 2010. The risk of dying after a diagnosis of DCIS is low, emphasizing the importance of treatment-related morbidity, yet the risk of recurrence remains substantial. Optimum individualized therapy remains elusive. We previously identified p53 overexpression as a biomarker for ipsilateral tumor recurrence (IBTR). The purpose of the current study was to investigate its prognostic validity in an expanded patient cohort with long-term follow-up.

Methods: We studied 186 consecutive pure DCIS patients from our Breast Cancer Registry and identified 142 cases with sufficient histopathologic material to perform evaluable immunostaining for p53. Median follow-up was 11 years. Statistical analysis was performed with SAS software.

Results: Median patient age was 66 (range 35-91) years and 47/153 (31%) presented with palpable disease. Median tumor size was 10 (range 2-165) mm. Predominant histologic subtype included 34 (24%) comedo, 43 (30%) solid, 50 (35%) cribiform and 15 (11%) micropapillary/papillary cases. Necrosis was present in 74/142 (52%) of tumors. Overexpression of p53 was identified in 33/142 (23%) and was associated with necrosis, but not with any other patient, tumor or treatment variables. Fifteen patients (11%) were diagnosed with an IBTR at a median of 56 (range 11-154) months after their initial diagnosis; 3 recurrences were DCIS, while 12 were invasive cancer. p53 overexpression, present in 10/15 (68%) of cases with recurrence versus 23/127 (18%) of non-recurrent tumors, p < 0.001, and no adjuvant tamoxifen, p = 0.003, were associated with IBTR. No other patient, tumor or treatment factors studied were predictive of IBTR. The type of IBTR did not correlate with the p53 status of the index tumor.

Conclusions: These data suggest that p53 may be a biomarker for elevated risk of IBTR after a diagnosis of DCIS and support the value of adjuvant tamoxifen for DCIS patients. Further investigation to validate these findings and to identify clinically useful individualized risk stratification for DCIS patients is warranted.
The novel cytotoxicity of neutrophils in the peripheral blood of breast cancer patients versus women without breast cancer.
Authors: Granot Z. , Comen E. A. , Norton L. , Benezra R.
Published: February 2017

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Background: Using murine mammary tumor models, recent research conducted by our laboratory at the Sloan-Kettering Institute indicates that select neutrophils are mobilized and entrained by a primary breast tumor and uniquely have the capacity to inhibit metastatic seeding in the lung (Granot Z et al. unpublished). We sought to determine whether entrainment of cytotoxic neutrophils also occurs in blood samples from women with newly diagnosed breast cancer as contrasted to those garnered from healthy women.

Methods: Subjects were 21 newly diagnosed pre-operative breast cancer patients without evidence of metastatic disease, 9 healthy female volunteers with no history of any cancer, and 3 patients with newly diagnosed DCIS. Neutrophils were purified from the blood samples. Cytotoxicity was evaluated by incubating isolated neutrophils with luciferase labeled MDA-MB-231 cells. Luciferase activity, as a reflection of % cell kill, was measured using a Bio-Tek microplate luminescence reader.

Results: Significant cytotoxicity was notably observed when MDA-MB-231 cells were co-cultured with neutrophils purified from patients with invasive tumors. Pre-operative breast cancer patients (n=21) had a cell kill range of 0-30% (mean = 12.1%), whereas healthy subjects (n=9) had a cell kill range of 0.2-8% (mean = 2.6%), p<0.004. DCIS patients (N=3) had a cell kill range of 3-4% (mean = 2.7).

Conclusions: To date, this preliminary work is the first to demonstrate the cytotoxic role of select neutrophils in the peripheral blood of breast cancer patients as contrasted with those from women without breast cancer. Further studies are needed to evaluate the prognostic and therapeutic role of cytotoxic neutrophils.
Effect of cyclooxygenase inhibition on CXCR3 ligand secretion in breast cancer.
Authors: Bronger H. , Kraeft S. , Stöckel A. , Welk A. , Kiechle M. , Schmitt M. , Schwarz-Boeger U. R. M.
Published: February 2017

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Background: In murine cancer models, the two IFN-γ inducible chemokines CXCL9 and CXCL10, those bind to the common receptor CXCR3, recruit NK cells and tumor-suppressive lymphocytes into the tumor site and impair tumor growth and metastatic spread. In human breast cancer (BC), we and others have shown that high levels of CXCL9 mRNA correlate with favorable prognosis and the number of infiltrating lymphocytes. Raising the intratumoral level of CXCR3 ligands might therefore be a feasible way to enhance the infiltration by tumor-suppressive immune cells and to improve immune intervention in breast cancer. Inhibition of cyclooxygenases (COX) has been shown to inhibit tumor growth and metastases formation in a lymphocytic and IFN-γ dependent manner. We therefore tested whether COX inhibition induces CXCR3 ligand secretion from breast cancer cells.

Methods: Human MCF-7 and MDA-MB 231 BC cells were stimulated with IFN-γ with or without prostaglandin E2 (PGE2) or COX inhibitors (indomethacin, aspirin, celecoxib). CXCL9 and CXCL10 release was measured by ELISA. COX-1 and COX-2 expression was measured in 45 BC samples and correlated with intratumoral CXCR3 ligand concentration.

Results: Prostaglandin E2 inhibits CXCL10 and CXCL9 release from breast cancer cells. Aspirin and indomethacin enhance the INF-γ mediated secretion of these CXCR3 ligands by inhibition of endogenous cyclooxygenases. Celecoxib has this effect only at low concentrations, at higher concentrations is shows PGE2 agonistic effects. In human breast cancer samples, COX-2 overexpression inversely correlates with CXCR3 ligand concentration, which shows that the mechanism of PGE2 induced CXCL9/CXCL10 suppression might also be relevant in vivo.

Conclusions: Suppressing endogenous PGE2 by cyclooxygenase inhibition increases CXCL9 and CXCL10 release from breast cancer cells and is therefore a feasible way to enhance the infiltration of breast tumors by tumor-suppressive lymphocytes. However, our results show that unselective COX inhibitors might be more suitable than the COX-2 specific celecoxib. Clinical trials are now warranted to clarify the mechanisms and therapeutic efficacy of COX inhibition in breast cancer.