bluuebunny/crossref_metadata_2025 huggingface dataset:
Interlaboratory Evaluation of a New Reverse Transcriptase Polymerase Chain Reaction–Based Enzyme-Linked Immunosorbent Assay for the Detection of Circulating Melanoma Cells: A Multicenter Study of the Dermatologic Cooperative Oncology Group
Authors: Reinhold U. , Berkin C. , Bosserhoff A.-K. , Deutschmann A. , Garbe C. , Gläser R. , Hein R. , Krähn G. , Peter R. U. , Rappl G. , Schittek B. , Seiter S. , Ugurel S. , Volkenandt M. , Tilgen W.
Published: February 2017

PURPOSE: Reverse transcription-polymerase chain reaction (RT-PCR)–based detection of tyrosinase mRNA is the most frequently used laboratory method for the detection of circulating tumor cells in melanoma patients. However, previously published results showed considerable variability in the PCR positivity rates.

MATERIALS AND METHODS: We designed a collaborative study to assess the sensitivity, specificity, and clinical relevance of a new standardized RT-PCR–based enzyme-linked immunosorbent assay (ELISA) for the detection of circulating melanoma cells. Blood samples of healthy donors mixed with cells of a melanoma cell line were prepared in a blinded fashion, and aliquots were sent to seven participating laboratories experienced in RT-PCR.

RESULTS: The results demonstrate a high sensitivity (1 melanoma cell/mL blood) and specificity (no false-negatives and 7.4% [2 of 28] false-positives) of the assay and a satisfactory rate of interlaboratory reproducibility. The analysis of aliquots of blinded samples derived from 60 melanoma patients identified tyrosinase mRNA in 17 of 60 (28.3%): three (20%) of 15 stage I patients, two (13.3%) of 15 stage II patients, five (35.7%) of 14 stage III patients, and seven (43.8%) of 16 stage IV patients. The interlaboratory reproducibility of positive samples, however, was extremely low and indicates the presence of low amounts of target mRNA.

CONCLUSION: Reverse transcriptase-PCR ELISA has a high sensitivity and specificity for the detection of tyrosinase mRNA in peripheral blood cells. The low interlaboratory reproducibility for the detection of tumor cells in blood samples of melanoma patients, however, raises the question of relevance of this assay for clinical use.
Combination Chemotherapy With Carboplatin and Docetaxel in the Treatment of Cancers of the Ovary and Fallopian Tube and Primary Carcinoma of the Peritoneum
Authors: Markman Maurie , Kennedy Alexander , Webster Kenneth , Peterson Gertrude , Kulp Barbara , Belinson Jerome
Published: February 2017

PURPOSE: Standard chemotherapy for advanced ovarian cancer currently includes a platinum agent (usually carboplatin) and paclitaxel. Because docetaxel is an active agent in platinum-resistant ovarian cancer, it is relevant to evaluate both the toxicity and efficacy of the combination of carboplatin and docetaxel in this clinical setting.

PATIENTS AND METHODS: The Gynecologic Oncology Program of the Cleveland Clinic Taussig Cancer Center conducted a phase II trial of carboplatin (area under the concentration-versus-time curve of 6) and docetaxel (60 mg/m2), delivered every 3 weeks for six courses, in patients with ovarian and fallopian tube cancers and primary carcinoma of the peritoneum who had either received no prior chemotherapy or had experienced a treatment-free interval of greater than 2 years before developing disease recurrence.

RESULTS: Fifty patients (median age, 57 years; range, 44 to 81 years) entered the trial (47 had had no prior chemotherapy). Our toxicity findings included the following: grade 4 neutropenia (64% of patients); hypersensitivity reactions (34%, none requiring discontinuation of therapy); peripheral neuropathy (6%). We had objective responses for 32 of 42 (81%) assessable patients.

CONCLUSION: The combination of carboplatin and docetaxel is highly active in ovarian cancer, with the major toxicity being bone marrow suppression. Hypersensitivity reactions are frequent but do not prevent continuation of treatment. With the dose and schedule employed in this trial, neurotoxicity is uncommon. Defining a role for this regimen in routine clinical practice will require the conduct of randomized controlled clinical trials.
Breaking Bad News About Cancer: Patients’ Preferences for Communication
Authors: Parker Patricia A. , Baile Walter F. , de Moor Carl , Lenzi Renato , Kudelka Andrzej P. , Cohen Lorenzo
Published: February 2017

PURPOSE: The goal of this study was to assess patients’ preferences regarding the way in which physicians deliver news about their cancer diagnosis and management.

PATIENTS AND METHODS: A sample of 351 patients with a variety of cancers completed a measure assessing their preferences for how they would like to be told news about their cancer. Patients rated characteristics of the context and content of the conversation as well as physician characteristics.

RESULTS: Factor analysis indicated that patients’ preferences for how they would like to be told news regarding their cancer can be grouped into the following three categories: (1) content (what and how much information is told); (2) facilitation (setting and context variables); and (3) support (emotional support during the interaction). Women (P = .02) and patients with higher education (P = .05) had significantly higher scores on the Content scale, women (P = .02) had higher scores on the Support scale, and younger patients (P = .001) and those with more education (P = .02) had higher scores on the Message Facilitation scale. Medical variables were not associated with patients’ ratings of the importance of the three subscales.

CONCLUSION: Patients rated items addressing the message content as most important, though the supportive and facilitative dimensions were also rated highly. Understanding what is important to patients when told news about their cancer provides valuable information that may help refine how this challenging task is best performed.
Accelerated-Intensified Cyclophosphamide, Epirubicin, and Fluorouracil (CEF) Compared With Standard CEF in Metastatic Breast Cancer Patients: Results of a Multicenter, Randomized Phase III Study of the Italian Gruppo Oncologico Nord-Ouest–Mammella Inter Gruppo Group
Authors: Del Mastro Lucia , Venturini Marco , Lionetto Rita , Carnino Flavio , Guarneri Domenico , Gallo Luigi , Contu Antonio , Pronzato Paolo , Vesentini Lorella , Bergaglio Marina , Comis Silvia , Rosso Riccardo
Published: February 2017

PURPOSE: To evaluate whether an accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) chemotherapy regimen with the support of granulocyte colony-stimulating factor (G-CSF) induces a higher activity and efficacy compared with standard CEF in metastatic breast cancer patients.

PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive as first-line chemotherapy either standard CEF (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2) administered every 21 days (CEF21) or accelerated-intensified CEF (cyclophosphamide 1,000 mg/m2, epirubicin 80 mg/m2, and fluorouracil 600 mg/m2) administered every 14 days (HD-CEF14) with the support of G-CSF. Treatment was administered for eight cycles.

RESULTS: A total of 151 patients were randomized (74 patients on the CEF21 arm and 77 on the HD-CEF14 arm). In both arms, the median number of administered cycles was eight. The dose-intensity actually administered was 93% and 86% of that planned, in CEF21- and HD-CEF14–treated patients, respectively. Compared with the CEF21 arm, the dose-intensity increase in the HD-CEF14 arm was 80%. Both nonhematologic and hematologic toxicities were higher in the HD-CEF14 arm than in the CEF21 arm. During chemotherapy, four deaths occurred in the HD-CEF14 arm. No difference in overall response rate (complete plus partial responses) was observed: 49% and 51% in the CEF21 and HD-CEF14 arms, respectively (P = .94). A slightly non–statistically significant higher percentage of complete response was observed in the HD-CEF14 arm (20% v 15%). No difference in efficacy was observed. The median time to progression was 14.3 and 12.8 months in the CEF21 and HD-CEF14 arms, respectively (P = .69). Median overall survival was 32.7 and 27.2 months in the CEF21 and HD-CEF14 arms, respectively (P = .16).

CONCLUSION: In metastatic breast cancer patients, an 80% increase in dose-intensity of the CEF regimen, obtained by both acceleration and dose intensification, does not improve the activity and the efficacy compared with a standard dose-intensity CEF regimen.
Impact of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography on Patient Management: First Year’s Experience in a Clinical Center
Authors: Tucker Robert , Coel Marc , Ko Jehoon , Morris Paul , Druger George , McGuigan Pat
Published: February 2017

PURPOSE: To measure the impact of whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET) on patient management during its first year of use in a community hospital.

MATERIALS AND METHODS: First-year FDG-PET impact was determined from 463 referring physicians’ evaluations of their patients’ PET imaging results using two surveys. Survey 1 was given to all physicians referring patients to PET to discover whether PET changed patient management or had decision-making value in the patient’s clinical algorithm. Survey 2 was given to one surgeon and one pulmonologist after therapy to determine how PET affected the surgical, chemotherapeutic, and/or radiotherapeutic treatment for the 53 cancer patients they referred.

RESULTS: The 463 responses to survey 1 described 23 different PET indications. Lung (40%), head and neck (18%), and colorectal cancers (11%) were the three leading causes of referral. PET changed patient management/therapy in 45% of all patients referred and had inferential/decision-making value in another 44%. Overall, PET had some type of positive influence in 412 (89%) of the patients. Survey 2 provided a more detailed assessment of 53 referrals from two specialists. PET positively affected surgery in 31 patients (58%), prompted the addition of chemotherapy or radiation therapy in nine patients (17%), and eliminated chemotherapy or radiation therapy in four cases (8%). Overall, PET affected patient management/therapy in 70% of the cases and had some decision-making value in another 26%, for a combined PET impact on patient management of 96%.

CONCLUSION: FDG-PET can be valuable for physicians in clinical practice. Its sensitivity and specificity in metabolic imaging, when combined with complementary anatomic imaging techniques, contribute significantly to the clinical treatment of cancer patients. In addition, the high accuracy of FDG-PET makes it a cost-effective radiologic procedure in the work-up of all suspected and/or recurrent cancer patients. Further research is needed to link this demonstrated impact on patient management to cost-effectiveness.
NSABP B-38: Definitive analysis of a randomized adjuvant trial comparing dose-dense (DD) AC→paclitaxel (P) plus gemcitabine (G) with DD AC→P and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer.
Authors: Swain Sandra M. , Tang Gong , Geyer Charles E. , Rastogi Priya , Atkins James Norman , Donnellan Paul P. , Fehrenbacher Louis , Azar Catherine A. , Robidoux Andre , Polikoff Jonathan , Brufsky Adam , Biggs David D. , Levine Edward A. , Zapas John L. , Provencher Louise , Perez Edith A. , Paik Soonmyung , Costantino Joseph P. , Mamounas Eleftherios P. , Wolmark Norman
Published: February 2017

LBA1000

Background: The primary aims were to determine whether adjuvant DD AC→PG will be superior to DD AC→P as well as to TAC in DFS and to compare the relative DFS of TAC and DD AC→P. Secondary endpoints include survival and toxicity. Methods: From Nov 3, 2004 to May 3, 2007, 4894 women were randomized; 1630 to TAC (docetaxel [T] 75 mg/m2, doxorubicin [A] 50 mg/m2, cyclophosphamide [C] 500 mg/m2 q3 wks x 6), 1634 to DD AC→P (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 followed by P 175 mg/m2 q2 wks x 4), and 1630 to DD AC→PG (A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 → P 175 mg/m2 + G 2000 mg/m2q2 wks x 4). Primary G-CSF support was required and erythropoiesis-stimulating agents (ESA) were used at investigator discretion. 52% were postmenopausal, 65% had 1 - 3 positive nodes, and 80% had HR+ breast cancer. Log-rank tests were used for pair-wise comparisons of the primary (DFS) and secondary (OS) endpoints among the three treatment arms. Results: With 64 months median follow-up, 5-year DFS in DD AC→PG group was 80.6% compared with 82.2% in DD AC→P group (HR=1.1; p=0.27) and 80.1 % (HR=0.97; p=0.71) in TAC group. 5-year OS was 90.8% in DD AC→PG group as compared with 89.1% (HR=.89; p=0.25) in DD AC→P group and 89.6 % (HR=0.90; p=0.32) in TAC group. HR for DFS and OS of DD AC→P vs. TAC were 0.89 (p=0.14) and 1.01 (p=0.92) respectively. Toxicities for TAC, DD AC→P, DD AC→PG, respectively: febrile neutropenia (Gr 3/4: 9%, 4%, 4% [p<0.001]), sensory neuropathy (Gr 3/4: <1%, 7%, 6% [p<0.001]), diarrhea (Gr 3/4: 8 %, 2%, 2% [p<0.001]). Hgb was <10 in 12%, 26%, 33% with ESA use in 35.2%, 47%, 51.6% and transfusions in 3.7%, 6.3%, 9.4%. Deaths on treatment: N=13, 5, 7 (p=0.2). AML/MDS: N=5, 8, 11. All cycles completed in 91% for TAC and 88% for DD regimens. Conclusions: Addition of G to DD AC→P did not improve outcomes. No significant differences in efficacy endpoints were identified between DD AC→P and TAC, though toxicity profiles differed. Funding: NCI PHS U10-CA-37377, -69974, -12027, -69651 and NCCTG U10-CA25224, with additional funding from Eli Lilly & Company, and Amgen, Inc.
Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC).
Authors: Bendell Johanna C. , Ervin Thomas J. , Senzer Neil N. , Richards Donald A. , Firdaus Irfan , Lockhart A. Craig , Cohn Allen Lee , Saleh Mansoor N. , Gardner Lesa R. , Sportelli Peter , Eng Cathy
Published: February 2017

LBA3501

Background: Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined P-CAP vs. CAP in pts with 2nd or 3rd line mCRC. This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763]). Based on these results, a randomized phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated. Methods: The study was a prospective, randomized, double-blind, placebo-controlled randomized phase III trial. Eligible pts had mCRC which was refractory to all standard therapies. Pts randomized 1:1 to Arm A = P-CAP (P 50 mg PO QD + CAP 1000 mg/m2PO BID d1-14) or Arm B = CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). Cycles were 21 days. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed. Results: Between 3/31/10 and 8/12/11, 468 pts were randomized, 234 pts were in each arm. Baseline demographics were balanced between the arms: age < 65y (A: 65%, B: 58.5%), male (A: 57.7%, B: 53.0%), ECOG PS 0 (A: 39.7%, B: 39.7%), K-ras mutant (A: 50.4%, B: 51.3%), and median number of prior therapies (A: 4, B: 4). As of 3/19/12, median follow up was 6.6 months. Median overall survival: Arm A = 6.4 mo, Arm B = 6.8 mo, HR 1.111 [0.905,1.365], p = 0.315. Median overall survival for K-ras WT pts: Arm A = 6.6 mo, Arm B = 6.8 mo, HR 1.020 [0.763,1.365], p = 0.894; K-ras mutant pts: Arm A = 5.4 mo, Arm B = 6.9 mo HR 1.192 [0.890,1.596], p = 0.238. Conclusions: Despite promising randomized phase II data, this phase III study shows no benefit in overall survival adding perifosine to capecitabine in the refractory colorectal cancer setting. Response rate, progression free survival, and safety data will be presented. Biomarker analysis is pending to see if subgroups of patients may have potential benefit.
Improving the efficacy of chemotherapy drugs for the treatment of triple-negative breast cancers.
Authors: Zoghi Behyar , Ravdin Peter
Published: February 2017

107

Background: Approximately 15-20% of all breast cancers account for triple-negative breast cancers that exhibit aggressive, distinct metastatic pattern and poor prognosis. More than 50% of patients with triple negative breast cancers develop chemoresistance and do not respond to chemotherapeutic drugs, leading to early relapse and shorter survival. Understanding the mechanisms underlying such resistance is therefore crucial for the development of new, efficacious cancer drugs. Methods: Through high-throughput miRNA inhibitor library screens, we have identified miRNA inhibitors that sensitize resistant triple negative breast cancer cells to paclitaxel, a drug commonly used to treat triple negative breast cancers. Results: Through high-throughput miRNA inhibitor library screens, we have identified miRNA inhibitors that sensitize resistant triple negative breast cancer cells to paclitaxel, a drug commonly used to treat triple negative breast cancers. Since miRNAs are endogenously expressed and can be easily manipulated using synthetic oligoribonucleotides, we believe that they represent more attractive targets than the single gene or gene product that is the target of conventional cancer treatments that are typically prone to drug resistance. Supporting this, we have recently demonstrated that miRNAs can be systemically delivered to treat breast cancer lung metastasis without any hepatotoxicity. In addition to being a potent therapeutic regimen, our preliminary analyses reveal that miRNAs can be bonafide early prognostic markers to monitor treatment response to specific drugs in triple-negative breast cancers. Conclusions: Taken together, these findings suggest that miRNA can serve as potent therapeutic adjuvants and although the data content of miRNA profiles is far less than that of gene expression profiles, by virtue of their ability to modulate entire spectrum of genes and pathways miRNAs have potential to be better classifiers for the prognosis and response to treatment of cancers. We believe that the identification of miRNAs that mediate chemoresistance could lead to more efficient treatment selection at the patient level and an improved response rates at the population level.
Characterization of responders versus nonresponders to the anti-estrogen agent fulvestrant: A retrospective cohort study.
Authors: Bhusal Santosh
Published: February 2017

117

Background: Patients with breast cancer often benefit from targeted endocrine therapy with estrogen receptor antagonists. However, the duration of therapeutic response to these agents is variable. We investigated several clinical variables that may potentially affect the duration of response to fulvestrant in the setting of metastatic disease. Methods: A retrospective cohort analysis was done in 137 patients who received fulvestrant between 2000 and 2011 at Moll Cancer Center at Fairview Hospital and Cleveland Clinic Cancer Center. Several patient variables e.g. degree of estrogen receptor positivity, BMI etc. were analyzed. The RECIST 1.1 criteria was used to measure disease activity. Clinical benefit (i.e., responsiveness) was defined as complete response, partial response or stable disease at 24 weeks of therapy. 57 patients had clinical benefit whereas 80 did not. The clinical variables were then compared between the two groups using Chi square test, Fisher's exact test and Wilcoxon’s rank sum test. A multivariable logistic regression model was then used to assess the association. Results: Patients who were responders exhibited a significantly higher proportion of bone and/or soft tissue only metastases than non-responders (51% vs. 24 %, p= 0.001). They also appeared to be older (mean age ± SD: 64.1 ± 12.2 vs. 60.2 ± 13.2, p=0.044) and had prior aromatase inhibitor sensitiveness (83% vs. 56, p=0.006). However, in multivariate and logistic regression analyses, the site of metastases was found to be the only significant predictor of response. Patients with bone and/or soft tissue only metastases were more likely to be responders than patients with visceral metastases (OR= 2.883 [95 % CI= 1.313 - 6.328], P= 0.012; OR: 3.325 [95% CI, 1.600-6.908], p=0.001, respectively). Conclusions: In metastatic breast cancer, patients with bone and/or soft tissue only metastases were more likely respond to fulvestrant therapy than those with visceral metastases.
Use of disseminated tumor cells to predict outcome in patients with stage I-III breast cancer.
Authors: Gainer Sarah Marie , Krishnamurthy Savitri , Bhattacharyya Anirban , Lodhi Ashutosh , Hall Carolyn S. , Bedrosian Isabelle , Kuerer Henry Mark , Lucci Anthony
Published: February 2017

119

Background: Published studies from Europe have shown the presence of disseminated tumor cells (DTCs) to independently predict outcomes in patients with non-metastatic breast cancer. The purpose of this study was to assess the experience with DTCs at a tertiary cancer center and to see if these cells indeed predict outcomes in patients with stage I-III breast cancer. Methods: Clinical stage I-III breast cancer patients seen at a single tertiary cancer center provided consent to participate in an IRB-approved study involving collection of bone marrow (5 ml x 2 tubes) at the time of surgery for their primary breast cancer. DTCs were assessed by anti-CK antibody cocktail (AE1/AE3, CAM5.2, MNF 116, CK 8 and 18) following cytospin. A positive result was defined as the presence of one or more cells per 5 ml of bone marrow. Statistical analyses used chi-square and Fischer’s exact tests. Results: Three hundred and sixty-six patients were prospectively enrolled. Mean age was 53 years. Median follow-up was 32 months. DTCs were identified in 109 patients (30%). Ten percent of patients with DTCs (11/109) and 3% of patients without DTCs (8/257) died (p = 0.009). Overall survival (OS) in patients with DTCs was 30 months vs. 31 months in those without DTCs. DTCs did not predict relapse free survival (P=NS). On multivariate analysis the presence of DTCs was an independent predictor of worse overall survival (p < 0.0001). No correlation was observed between the presence of DTCs and lymph node metastases and/or other clinicopathologic variables. Conclusions: The presence of DTCs was an independent predictor of worse OS in patients with stage I-III breast cancer. Consideration should be given to the utilization of DTCs as predictors of outcome in clinical practice.
Comparison of the incidence of peripheral neuropathy (PN) with eribulin versus ixabepilone (IXA) in metastatic breast cancer (MBC) patients: A randomized phase II study.
Authors: Vahdat Linda T. , Garcia Agustin , Vogel Charles L. , Pellegrino Christine M. , Lindquist Deborah L. , Sparano Joseph A. , Gopalakrishna Prashanth , Iannotti Nicholas
Published: February 2017

121

Background: Eribulin mesylate is approved for patients (pts) with MBC who have previously received ≥2 chemotherapeutic regimens for metastatic disease including an anthracycline and taxane in either the adjuvant or metastatic setting. This study compared incidence and severity of neuropathy adverse events (AEs) in pts receiving eribulin or IXA. Methods: Pts (locally recurrent/MBC; prior taxane therapy; ≥1 prior chemotherapy for advanced disease; pre-existing neuropathy Grade 0 [n=51] or 1 [n=53]) were randomized to receive 1.4 mg/m2 eribulin mesylate (2–5-min intravenous (IV), Days 1 and 8 of a 21-day cycle) or 40 mg/m2IXA (3 h IV, Day 1 of a 21-day cycle). The primary objective was to compare incidence of neuropathy AEs by CTCAE grade. Secondary objectives: severity of neuropathy AEs by CTCAE grade, patient neurotoxicity questionnaire (PNQ), and vibration sensitivity using Vibration Perception Threshold (VPT); time to onset of treatment-emergent neuropathy (TEN); efficacy; safety and tolerability. Results: Incidences ofPN and TEN (all grades) with eribulin (n=51) versus (vs) IXA (n=50) were 31.3% vs 44.0%, p=0.1632 and 33.3% vs 48.0%, p=0.1284, respectively. Severity (grade ≥3) was numerically lower with eribulin than IXA (PN: 9.8% vs 20.0%; TEN: 9.8% vs 22.0%). No significant differences were seen in baseline to worst PNQ scores. Median worst post-baseline VPT scores were lower with eribulin than IXA (index finger: 2.3 vs 2.4 vibration units [vu]; great toe: 7.75 vs 8.6 vu). Median time to onset of TEN was earlier with IXA (11.6 weeks [wks]) than eribulin (35.9 wks). TEAEs were comparable. Median treatment duration was 15.0 wks (eribulin) and 10.5 wks (IXA). Reasons for discontinuation (eribulin vs IXA): TEN (3.9% vs 18.0%); any TEAE (11.8% vs 32.0%); progressive disease (68.6% vs 48.0%). Objective response and clinical benefit rates were 15.4% vs 5.8% and 26.9% vs 19.2% for eribulin and IXA, respectively. Conclusions: Although not statistically significant, neuropathy AEs were less common with eribulin than IXA. Eribulin was associated with longer time to onset of TEN and fewer discontinuations due to neuropathy and other toxicities.
Feasibility of two schedules of weekly paclitaxel as (neo)adjuvant treatment for patients (PTS) with HER2-negative breast cancer (BC) in the Brazilian community setting.
Authors: Santana Iuri Amorim , De Oliveira Julia Andrade , Amaral Alan Alves , Testa Laura , Landeiro Luciana Garcia , Costa Romulo Leopoldo de Paula , Hajime Marcelo , Ferrari Marcela Simonis Martins , Petry Vanessa , Heinemann Cohn Daniela J. B. , Hoff Paulo M. , Mano Max S.
Published: February 2017

122

Background: Paclitaxel is one of the most active drugs in BC and the weekly administration has been shown more effective and better. GEICAM9906 was a phase III trial that demonstrated the effectiveness and safety of a pragmatic dose-dense schedule of 100mg/m2 of paclitaxel given over 8 consecutive weeks (w), without G-CSF support. This schedule has been adopted at our institution in 2009 for HER2 negative disease and herein we present the first off-trial experience and also compare its safety profile with that of a historical cohort of pts treated with the conventional 80mg/m2 x12w schedule. Methods: The study consists of a retrospective review of medical files from pts with locally advanced BC treated with (neo)adjuvant paclitaxel-based therapy with one of two schedules: (1) 80 mg/m² x 12w or (2) 100 mg/m² x 8w. Adverse events (AE) were graded according to Common Terminology Criteria for Adverse Events 4.0 (CTCAE). Results: We reviewed files from 326 women with a median age of 52 (±10.9). Seventy and 256 pts received schedule (1) and (2), respectively. No significant difference was observed in the incidence of G3/4 toxicity: pneumonitis (2.8% vs 0.3% p=0.097), neuropathy (2.8% vs 0.7% p=0.303); hand-foot syndrome (1.4% vs 0.3% p=0.538); anaemia (0 vs 0.6% p=0.624); neutropenia (5.7% vs 6.2% p=0.408) with only one case of febrile neutropenia in schedule (2) arm; without cases of grade 3/4 thrombocytopenia, nausea, mucositis or anaphylaxis in both groups. Also, no significant difference was seen when comparing all grades toxicty. The dose intensity of paclitaxel was higher in schedule (2) with 97.72 mg/m² per week vs 77.07 mg/m² per week (p<0.0001). Conclusions: Weekly paclitaxel given according to GEICAM9906 is a pragmatic and well tolerated schedule when used in the Brazilian community setting, with a safety profile comparable to the conventional 80mg/m2 x12w schedule. In addition to being convenient to pts, it may also be cost-effective because of a lower number of clinic visits and infusions.
Characterization of the overall survival benefit in ENCORE 301, a randomized, placebo-controlled phase II study of exemestane with and without entinostat in ER+ postmenopausal women with metastatic breast cancer.
Authors: Klein Pamela , McCulloch William , Ordentlich Peter , Cruickshank Scott , Rees Miranda , Yardley Denise Aysel
Published: February 2017

128

Background: Histone deacetylase inhibitors (HDACi) prevent the emergence of drug tolerant clones and sensitize cells to a variety of anti-cancer therapies. We previously reported ENCORE 301, a randomized placebo controlled phase II study comparing exemestane with (EE) and without (EP) the HDACi entinostat met its primary endpoint of prolonging progression free survival (PFS) (4.3 months vs 2.3 months) and extending overall survival (OS) benefit (26.9 vs 19.8 months). In order to characterize and better understand the OS benefit, exploratory analyses were conducted. Methods: Hazard ratios (HR) for treatment were estimated from the Cox proportional hazards model, with EP serving as the reference treatment in the calculations. Inferential comparisons between treatment groups were made using the log-rank test. Results: Analysis of OS across multiple subsets of interest demonstrated a consistent benefit in EE group versus EP. Sensitivity analysis of baseline characteristics potentially impacting OS did not identify any factors that influenced the effect of EE on OS. Examination of treatments received during follow-up after discontinuation of EE and EP demonstrated balance between treatment group for patients receiving chemotherapy (48% EE: 44% EP), hormone therapy (37% EE: 35% EP), bisphosphonates (2% EE; 0% EP), radiation (6% EE; 5%EP), and surgery (0% EE: 2% EP). Compared to EP, OS was longer in EE group for patients whose first subsequent treatment was a hormone therapy (EE median not reached vs EP median 20.5 months; HR 0.65 [95% CI 0.26, 1.58]) or chemotherapy (EE median 26.9 months vs EP median 17.6 months; HR 0.51 [95% CI 0.25, 1.04]). Updated PFS and OS data will also be presented along with correlation analysis of PFS and OS. Conclusions: Analyses of baseline characteristics, subsequent treatment and subsets of prognostic factors in ENCORE 301 did not identify any contributing factors that account for the extended OS benefit in the EE treatment group. Long lasting effects of entinostat on progenitor cells, emergence of drug tolerant cells and or priming to subsequent therapies cannot be ruled out.
Optimizing breast cancer diagnosis in Kenya: Importance of standardization of technical methodologies for comparative breast cancer data.
Authors: Sayed Shahin , Moloo Zahir , Wasike Ronald , Chauhan Rajendra R. , Vinayak Sudhir , Karanu Joseph , Bird Peter , Njoroge Wambui , Nzioka Ancent , Gachii Andrew , Chumba David , Otieno James Obondi , Mohamed Musa , Al-Ammary Ammar , Sherman Omar , Prasad Satya , Kyobutungi Catherine , Saleh Mansoor N.
Published: February 2017

139

Background: An analysis of 322 cases referred to Aga Khan University, Nairobi, revealed 56% estrogen receptor (ER) positive tumors and 35% prevalence of triple-negative breast cancer (TNBC). Findings were retrospective and limited by inability to control pre-analytical variables that could potentially impact results. Methods: As part of an ongoing prospective study assessing prevalence of TNBC in the three major ethnic groups in Kenya, we gathered a multidisciplinary team from 10 collaborating health facilities around Kenya for an educational workshop. The objectives were to assess baseline capabilities and pre-analytic variables at each center, identify gaps and provide hands-on training in order to ensure accuracy and validity of ER/PR/HER2 prevalence data gathered as part of the study. Results: See table. Breast cancer biopsies ranged from one to 20 per month per center. Diagnosis was predominantly by FNA and ER/PR/HER2 was not routinely performed. Buffered formalin fixative and standardized CAP reporting format was employed only at one center. A survey 3 months following the workshop demonstrated increase in diagnostic core biopsiesby 90%, and uniform use of buffered formalin fixative, and adoption of synoptic reporting. 66 prospective cases of breast cancer from the 10 institutions with patients from different ethnic backgrounds have been subsequently collected and IHC data will be presented. Conclusions: Much has been made of the difference in prevalence of TNBC in Africa as compared to North America, yet little attention has been paid to differences in diagnostic methodologies and basic tissue handling techniques that can potentially alter results. Despite limitations of resources, educational workshops make it possible to improve the practice of breast cancer diagnosis, and thereby enable accurate comparative analysis between breast cancers in the developing and the developed world. [Table: see text]
Ki-67, p53, and clinical outcomes of patients with triple-negative breast cancer.
Authors: Nishiyama Yasuyuki , Nishimura Reiki , Osako Tomofumi , Okumura Yasuhiro , Arima Nobuyuki
Published: February 2017

142

Background: Triple-negative breast cancer (TNBC) tends to produce a poor prognosis because of aggressive tumor biology and lack of targeted agents. Breast cancer with a high Ki-67 value responds better to chemotherapy but is associated with lower relapse-free (RFS) and overall survival rates. The basal-like subtype overlaps with TNBC in approximately 70% to 80% of the cases, and the vast majority of basal-like subtypes have mutated p53. The aim of this study was to evaluate the clinical and prognostic significance of Ki-67 and p53 in patients with TNBC. Methods: We retrospectively reviewed 1,711 patients with pT1-3 invasive breast cancer diagnosed between 2001 and 2010. Of the 200 TNBC cases, 165 patients received adjuvant chemotherapy. Cases were classified as luminal (ER+ and/or PR+ and HER2-), HER2 disease (HER2+) and TNBC (ER-, PR- and HER2-) subtypes. Estrogen receptor (ER) and progesterone receptor (PR) positivity was defined as ≥10% positive tumor cells with nuclear staining. Ki-67 was classified into the following three groups: low (<20%), intermediate (20-50%) and high (≥50%), and the p53 high group was indicated by ≥50% staining. RFS was compared according to the level of Ki-67 and p53. Results: Patients with a high Ki-67 value were frequently seen in 53% of the cases with TNBC (luminal: 6% and HER2 disease: 25%, p<0.0001). The greatest proportion of patients in the low p53 group were the luminal type (luminal: 7%, HER2 disease: 49%, TNBC: 54%, p<0.0001). A high Ki-67 value was not associated with poor RFS in TNBC (p=0.2734). A high p53 expression was associated with poor RFS (p=0.024). TNBC with adjuvant chemotherapy and a high p53 expression tended to produce poor RFS (p=0.0516). Conclusions: TNBC with a high Ki-67 value was not associated with poor prognosis in this study. However, p53 status could be a significant prognostic factor in TNBC patients, especially in adjuvant chemotherapy cases.
Evaluation of current consensus panel guidelines for APBI: A pooled analysis of William Beaumont Hospital and American Society of Breast Surgeons MammoSite registry trial data.
Authors: Wilkinson John Ben , Beitsch Peter D. , Arthur Douglas W. , Shah Chirag , Haffty Bruce George , Wazer David E. , Keisch Martin , Shaitelman Simona Flora , Lyden Maureen , Vicini Frank
Published: February 2017

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Background: To determine whether the ASTRO Consensus Panel (CP) guidelines for accelerated partial breast irradiation (APBI) are associated with significantly different outcomes in a pooled analysis from William Beaumont Hospital (WBH) and the American Society of Breast Surgeons (ASBrS) MammoSite Registry Trial. Methods: 2,127 cases of early-stage breast cancer were treated using APBI (WBH: n=678; ASBrS: n=1,449). Three forms of APBI were used at WBH (interstitial, n=221; balloon-based, n=255; or 3D-CRT, n=206) while all Registry Trial patients received balloon-based brachytherapy. Patients with complete coding necessary for ASTRO CP assignment (n=1,813) were divided into suitable (n=661, 36.5%), cautionary (n=850, 46.9%), and unsuitable (n=302, 16.7%) categories. Tumor characteristics and clinical outcomes were analyzed according to CP group. Results: Median age was 65 years (32-94 years) and median tumor size was 10.0mm (0-45mm). The WBH cohort had more node-positive disease (6.9% vs. 2.6%, p<0.01) and cautionary patients (49.5% vs. 41.8%, p=0.06). Five-year rates of ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), and distant metastasis (DM) for the whole cohort were 2.8%, 0.6%, 1.6%, respectively. When analyzed by CP group, the rate of IBTR was not statistically higher for suitable (2.5%), cautionary (3.3%), or unsuitable (4.6%) patients (p=0.20). The non-significant increase in IBTR for grouped cautionary/unsuitable categories was due to increased elsewhere failures/new primaries (p=0.04), not true recurrences (1.1-1.2%, all groups, p=0.94). A higher rate of DM was observed within the cautionary and unsuitable groups (3.3-3.6% vs. 0.7% for suitable, p=0.01), although cause-specific survival was the same for all patient categories (98.0-98.6%, all groups, p=0.47). Conclusions: Excellent outcomes following breast conserving surgery and APBI were seen in our pooled analysis. The current ASTRO CP guidelines did not adequately differentiate patients at an increased risk of IBTR or tumor bed failure within the largest patient population of cases treated with APBI to date.
Impact of the number of cautionary/unsuitable risk factors on outcomes following accelerated partial breast irradiation.
Authors: Wilkinson John Ben , Wobb Jessica , Shah Chirag , Fowler Ashley , Mitchell Christina , Wallace Michelle , Grills Inga S. , Stromberg Jannifer S. , Vicini Frank , Chen Peter Y.
Published: February 2017

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Background: Current guidelines for APBI stratify appropriateness of treatment outside of a clinical trial. Limited data are available, however, regarding the impact of the number of risk factors (RFs) per patient on clinical outcomes. Methods: 692 patients were treated with APBI at a single institution between 10/1992 and 10/2011. Patients were stratified by the ASTRO guidelines as suitable, cautionary, and unsuitable. Outcomes including ipsilateral/contralateral breast tumor recurrence (IBTR/CBTR), regional recurrence (RR), distant metastases (DM), disease-free survival (DFS), cause specific survival (CSS), and overall survival (OS) were evaluated by risk group and number of RFs. Results: Median follow-up was 5.2 years (range: 0-18.3).Distribution within CP risk-groups was suitable: 240, cautionary: 343, and unsuitable: 109 patients. Increased IBTR (2.0% v. 0.6%, p=0.03), DM (6.5% v. 1.5%, p=0.02), and decreased DFS (92% v. 98%, p=0.01) were noted for patients with 2+ cautionary RFs (n=115) vs. 1 RF (n=228). Those with 2+ unsuitable RFs had higher RR (7.7% v. 1.7%, p=0.05). Pooled analysis revealed increased IBTR/RR for patients with 3+ combined cautionary/unsuitable RFs vs. 2 or fewer combined RFs (Table). Univariate analysis showed increased DM with increasing tumor size/T-stage (p<0.01), ER negativity (p=0.04), LVSI (p=0.01), + LN (p<0.01), and increasing number of RFs (p<0.01). No single RF was associated with an increased risk of local recurrence on UVA. Conclusions: Three or more cautionary or unsuitable APBI RFs is associated with higher local, regional, and distant recurrence. Patients with fewer than 3 total RFs have a 98% locoregional control at 5 years and likely remain good candidates for APBI. Future attempts to risk stratify patients may need to account for the number of RF present in order to appropriately classify patients. [Table: see text]
Age, hormone receptor status, ethnicity, and adjuvant radiation therapy as predictive factors for cancer-related death in patients age 70 and older with early-stage pT1a,b N0 breast cancer: An NCI-SEER database analysis.
Authors: Ravi Akkamma , Christos Paul J. , Nori Dattatreyudu , Chao Clifford , Yan Weisi
Published: February 2017

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Background: Studies have shown that older women are undertreated for breast cancer. Few data are available on 1) cancer-related death in elderly women age 70 and older with pathologic stage T1a, bN0 breast cancer and 2) on the impact of prognostic factors such as increasing age, hormone receptor status (ER), adjuvant radiation therapy (EBRT), chemotherapy, and ethnicity on cancer-related death. Methods: Patient data from SEER database were extracted. Inclusion criteria: females, age 70 and older, pT1a, bN0 invasive breast cancer, ER positive or negative, adjuvant EBRT or no radiation. Cause-specific survival time recorded for all eligible patients. Log-rank test and multivariate Cox regression analysis used for statistical analysis. Hazard ratios (HR) are presented for cancer-related death. Results: ER negative patients had a greater risk of breast cancer death compared to ER positive patients (adjusted HR = 2.34; p < 0.0001). Stage IB patients had a greater risk of breast cancer death compared to stage IA patients (adjusted HR = 1.26; p = 0.09; trend). Patients with no radiation therapy had a greater risk of breast cancer death compared to patients with radiation therapy (adjusted HR = 1.40; p = 0.003). Older age groups had greater risk of breast cancer death compared to patients age 70-74 (referent category) (adjusted HR’s = 1.41, 1.72, and 3.18 for 75-79, 80-84, and 85+ age groups, respectively) (Table). Race had no effect on survival. Conclusions: Patients age 75 and older with T1a, b N0, ER-negative, breast cancer had increased risk of breast cancer-related death. Adjuvant EBRT showed survival benefit in this elderly patient population. Future randomized studies should focus on adjuvant treatments that will improve cancer-related death in this age group. [Table: see text]
Comparison of long-term results of endoscopic video-assisted breast surgery (VABS) between trans-axillary retro-mammary appcoach (TARM) and periareolar approach.
Authors: Yamashita Koji , Shimizu Kazuo , Haga Shunsuke
Published: February 2017

167

Background: The breast conserving surgery (BCS) and the sentinel node (SN) biopsy became to be recognized as the standard treatment for early breast cancers. We have reported about cosmetic effectiveness and lower infestation of the video-assisted breast surgery (VABS) for the breast diseases. We devised the trans-axillary retro-mammary (TRAM) approach of VABS. It needs only one skin incision in the axilla and can treat any tumor of the breast without making any injuries on the breast skin. We evaluated the aesthetic results and the curability of this surgical method. Methods: We have performed VABS on 300 patients since December 2001. The newly devised TARM was performed on 120 patients of early breast cancer, stage I and II. After endoscopic SN biopsy, we elongated the axillary skin incision to 2.5 cm. We dissected major pectoral muscle fascia to detach retromammary tissue behind the tumor. We cut the mammary gland with clear surgical margin, and removed it through the axillary port. The breast reconstruction was made by filling absorbable oxydized cellulose. The postoperative aesthetic results were evaluated by ABNSW. Results: BCS was performed on 286 patients (26 after preoperative chemotherapy) and skin-sparing mastectomy on 14. There was no serious complication after surgery. Surgical margin was minimally positive in 2. The original shapes of the breast were preserved well. The follow-up is 126 months at maximum and 74 months on average. There is 3 locoregional recurrences and 14 distant metastases. 5-year survival rate is 97.3%. With regard to TARM, The skin incision only in the axilla made better looks and shapes of the breast. It could be applied for tumors in any area of the breast without tumor nipple extension. The reconstruction with oxidized cellulose needs no excessive detachment of the skin beyond the surgical margin. The postoperative esthetic results were excellent and better. The sensory disturbance was minimal. All patients expressed great satisfaction. Conclusions: VABS can be considered as a good surgical procedure concerning locoregional control and esthetics. TARM is better on the patients without tumor nipple extension.
Hypofractionated breast irradiation in elderly cancer parients: A Brazilian pilot study.
Authors: Campos Conceicao Souza
Published: February 2017

178

Background: In 2025, Brazil will be the 6th country in the world with the most aged population represented by elderly (15% above 60 years). Nowadays, life expectance is around 65 years old and there is not sufficient data about cancer management in the elderly. Breast cancer is generally detected in more advanced stages and not well treated due to the other medical conditions. The hypofractionation garantees the same local control with mild acute reactions and no functional late complications in a shorter treatment time. Methods: The pilot study addressed the acute local morbidid and the local control of fourteen patients (stages I to III), median age 78 years that received one single 6.5 Gy weekly dose in 5-7 fractions with 6MV photons or 6MéV electrons to the breast or thoracic grid using tangential fields or direct field, accordingly to the patients anatomy (from August 2006 to April 2008). The total dose ranged from 32.5 Gy to 45.5 Gy. The supraclavicular nodes were treated if >= 4 axillary nodes were positive (3/14). Modified mastectomy was the most frequent surgical procedure (9/14). Node negative disease was discovered in seven patients, T2 lesions in eight, invasive ductal carcinoma in nine and positive estrogen receptor in ten. Ten patients had comorbid diseases, the most frequent was high blood pressure. The patients had weekly skin evaluation and were scored accordingly to the RTOG score. The patients were followed in consultation until April 2012. Results: Two cases of erithema were observed after the completion of the treatment. These patients received seven fractions due to boost at surgical bed. The other patients didn't show any acute reactions. To date we observed an early infraclavicular failure after the completion of the radiotherapy. There were two cases of fat necrosis and two fibrosis. There was only one local failure and a second primary in the contralateral breast. Conclusions: The hypofractionated scheme showed good skin tolerance. A longer follow-up is needed for evaluation of local recurrence. We have to consider irradiation of the supraclavicular area in the case of any positive axillary node. The hypofractionation irradiation is a good treatment option for elderly breast cancer patients (> 70 years).
The CXCL7/CXCR2 axis and the migration of breast cells toward the malignant phenotype.
Authors: Kosr Mary Ann , Ju Donghong
Published: February 2017

181

Background: A component of the epithelial to mesenchymal transition (EMT) is degradation of extracellular matrix and acquisition of migration, both of which support invasiveness. The expression of CXCL7 is associated with the invasive phenotype through interaction with the CXCL7/CXCR2 axis and heparan sulfate. The purpose of this study is to quantify the expression of genes associated with EMT by CXCL7-expressing cells with the migration/invasive phenotype. Methods: Total RNA from CXCL7-transfected breast cells (MCF10AT) was tested for relative gene expression using RT2 Profiler PCR array for EMT (SABiosciences). Vector transfected cells were compared. Each result was verified by real time PCR assay. In parallel, migration assays were performed quantitatively using transwell membranes and qualitatively with the scratch test and photodocumented. Results: The expression of GNG11 and TCF4 was upregulated and SPP1 downregulated as expected for the EMT profile. Specifically, GNG11 (Guanine nucleotide binding protein (G protein), gamma 11) expression was increased 2.94 fold and TCF4 (Transcription factor 4) increased 1.89 fold. The expression of SPP1 (Secreted phosphoprotein 1) was decreased by 6.8 fold. The expression of ZEB2 (Zinc finger E-box binding homeobox 2) was decreased by 1.96 as a transcription factor. Migration of CXCL7-transfectants was significantly increased over vector controls and comparable to invasive isogenic breast cancer cells. Conclusions: The CXCL7-transfected cells with invasive phenotype express genes associated with the EMT expression profile including G-protein signaling pathway.