bluuebunny/crossref_metadata_2025 huggingface dataset:
When Is a Tumor Marker Ready for Prime Time? A Case Study of c-erbB-2 as a Predictive Factor in Breast Cancer
Authors: Yamauchi Hideko , Stearns Vered , Hayes Daniel F.
Published: February 2017

PURPOSE: c-erbB-2 (HER-2, c-neu) might play a role as a predictive factor in breast cancer. However, the clinical utility of the marker in this disease is still not established. We conducted a critical analysis of the literature, in which we reviewed the factors that contribute to the lack of acceptance of c-erbB-2 for clinical use and attempted to determine the predictive role of c-erbB-2 for response to specific therapies.

METHODS: We conducted a MEDLINE literature search using the keywords c-erbB-2, HER2, neu, and breast cancer, reviewed the references included in each publication, and reviewed abstracts that have been reported in the 1997-2000 proceedings to the American Association of Cancer Research and American Society for Clinical Oncology annual meetings.

RESULTS: The preclinical and clinical data reported to date suggest that amplification or overexpression of c-erbB-2 is a weak to moderate negative pure prognostic factor. c-erbB-2 seems to be a weak to moderate negative predictive factor for response to endocrine therapy. The marker is also a moderate negative predictive factor for response to alkylating agents and a moderate positive predictive factor for response to anthracyclines. The data regarding response to taxanes or radiotherapy are not sufficient to make recommendations regarding treatment decision making. Finally, c-erbB-2 is a strong predictive factor for response to trastuzumab.

CONCLUSION: We conclude that, in the adjuvant setting, c-erbB-2 status should not be used to determine whether a woman should receive adjuvant systemic therapy (weak prognostic factor). In addition, c-erbB-2 status should not be used to determine whether a patient should receive endocrine therapy. When adjuvant chemotherapy is recommended, anthracycline-based therapy should be the preferred regimen for c-erbB-2–positive patients. However, when anthracyclines are contraindicated, alkylating agent–based therapy should not be withheld. To determine the true predictive role and strength of the marker for response to each therapy, prospective randomized clinical trials or formal meta-analyses are required.
Outcomes of Treatment of Children and Adolescents With Recurrent Non-Hodgkin’s Lymphoma and Hodgkin’s Disease With Dexamethasone, Etoposide, Cisplatin, Cytarabine, and l-Asparaginase, Maintenance Chemotherapy, and Transplantation: Children’s Cancer Group Study CCG-5912
Authors: Kobrinsky Nathan L. , Sposto Richard , Shah Narayan R. , Anderson James R. , DeLaat Cynthia , Morse Margaret , Warkentin Phyllis , Gilchrist Gerald S. , Cohen Mervyn D. , Shina Donald , Meadows Anna T.
Published: February 2017

PURPOSE: To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and l-asparaginase (DECAL) for recurrent non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD).

PATIENTS AND METHODS: Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy.

RESULTS: After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% ± 9% and 23% ± 5% in patients with HD and NHL, respectively. Five-year survival was 31% ± 14% and 30% ± 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P = .002; survival, P = .011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach.

CONCLUSION: DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.
Alternating Hepatic Arterial Infusion and Systemic Chemotherapy for Liver Metastases From Colorectal Cancer: A Phase II Trial Using Intermittent Percutaneous Hepatic Arterial Access
Authors: Copur M. Sitki , Capadano Mary , Lynch James , Goertzen Timothy , McCowan Timothy , Brand Randall , Tempero Margaret
Published: February 2017

PURPOSE: To evaluate the objective response to a short course of hepatic arterial infusion (HAI) using temporary, percutaneously placed catheters alternating with systemic prolonged continuous infusion fluorouracil (ci 5-FU) and daily oral leucovorin (L).

PATIENTS AND METHODS: Eligible patients were previously untreated (except for adjuvant therapy) adults with liver-predominant metastases, with Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment regimen included HAI with fluorodeoxyuridine (FUDR) 60 mg/m2/d and L 15 mg/m2/d continuously infused daily for 4 days. After a 1-week rest, ci 5-FU was administered through a central venous access device using a dose of 180 mg/m2/d with a fixed dose of oral L at 5 mg/m2/d for 21 out of 28 days. Cycles were repeated every 6 weeks. After four cycles of therapy, patients were maintained on ci 5-FU and daily oral L until evidence of progression.

RESULTS: Forty-three patients were enrolled onto this trial. One patient was ineligible. The objective response rate for all patients (17 partial, zero complete) was 41% (95% confidence interval [CI], 26% to 56%). Five patients were not able to receive at least one complete cycle of HAI. Among patients who received at least one complete cycle of HAI, the response rate was 46% (95% CI, 30% to 62%). Five patients underwent a liver resection after enrolling onto the protocol. At the time of analysis, estimated median time to progression was 6 months, and estimated median overall survival was 13 months.

CONCLUSION: The objective response rate was comparable to that achieved with more prolonged and more frequent HAI using FUDR. This approach should be studied as an acceptable alternative to surgically placed hepatic arterial catheters/pumps and may have a role as neoadjuvant therapy for liver metastases that are unresectable, as well as an adjuvant role for patients with resected hepatic metastatic colorectal cancer.
Fluorouracil Modulation in Colorectal Cancer: Lack of Improvement With N -Phosphonoacetyl- l -Aspartic Acid or Oral Leucovorin or Interferon, But Enhanced Therapeutic Index With Weekly 24-Hour Infusion Schedule—An Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study
Authors: O’Dwyer Peter J. , Manola Judith , Valone Frank H. , Ryan Louise M. , Hines John D. , Wadler Scott , Haller Daniel G. , Arbuck Susan G. , Weiner Louis M. , Mayer Robert J. , Benson Al B.
Published: February 2017

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer.

PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years.

RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P < .001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly.

CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.
Bexarotene Is Effective and Safe for Treatment of Refractory Advanced-Stage Cutaneous T-Cell Lymphoma: Multinational Phase II-III Trial Results
Authors: Duvic Madeleine , Hymes Kenneth , Heald Peter , Breneman Debra , Martin Ann G. , Myskowski Patricia , Crowley Connie , Yocum Richard C. ,   for Members of the Bexarotene Worldwide Study Group
Published: February 2017

PURPOSE: Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL.

PATIENTS AND METHODS: Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d.

RESULTS: Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache.

CONCLUSION: Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.
Detection of Chromosome Abnormalities Pre–High-Dose Treatment in Patients Developing Therapy-Related Myelodysplasia and Secondary Acute Myelogenous Leukemia After Treatment for Non-Hodgkin’s Lymphoma
Authors: Lillington Debra M. , Micallef Ivana N.M. , Carpenter Emily , Neat Michael J. , Amess John A.L. , Matthews Janet , Foot Nicola J. , Young Bryan D. , Lister T. Andrew , Rohatiner Ama Z.S.
Published: February 2017

PURPOSE: To assess whether pre–high-dose therapy (HDT)–related factors play a critical role in the development of therapy-related myelodysplasia (tMDS) or secondary acute myelogenous leukemia (sAML).

PATIENTS AND METHODS: Twenty-nine of 230 patients with a primary diagnosis of non-Hodgkin’s lymphoma (NHL) developed tMDS/sAML after HDT comprising cyclophosphamide and total-body irradiation (TBI) supported by autologous hematopoietic progenitor cells. G-banding and fluorescence in-situ hybridization (FISH) were used to detect clonal cytogenetic abnormalities.

RESULTS: The majority of patients showed complex karyotypes at diagnosis of tMDS/sAML containing, in particular, complete or partial loss of chromosomes 5 and/or 7. Using single locus–specific FISH probes, significant levels of clonally abnormal cells were found before HDT in 20 of 20 tMDS/sAML patients screened, compared with three of 24 patients screened who currently have not developed tMDS/sAML, at a median follow-up of 5.9 years after HDT.

CONCLUSION: Prior cytotoxic therapy may play an important etiologic role and may predispose to the development of tMDS/sAML. Using a triple FISH assay designed to detect loss of chromosomal material from 5q31, 7q22, or 13q14, significant levels of abnormal cells can be detected before HDT and may predict which patients are at increased risk of developing secondary disease. Further prospective evaluation of this FISH assay is warranted to determine its predictive power in this setting.
Phase II Study of Docetaxel, Estramustine, and Low-Dose Hydrocortisone in Men With Hormone-Refractory Prostate Cancer: A Final Report of CALGB 9780
Authors: Savarese D.M. , Halabi S. , Hars V. , Akerley W.L. , Taplin M-E , Godley P.A. , Hussain A. , Small E.J. , Vogelzang N.J.
Published: February 2017

PURPOSE: To investigate the combination of docetaxel, estramustine (EM), and low-dose hydrocortisone in men with hormone-refractory prostate cancer (HRPC).

PATIENTS AND METHODS: Combinations of EM with other antimitotic agents such as docetaxel are synergistic in vitro and show significant clinical activity in patients with HRPC. We studied intravenous administration of docetaxel 70 mg/m2, oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy.

RESULTS: Of the 47 men enrolled onto this multicenter cooperative group study, 46 were assessable for response and/or toxicity. In the 24 patients with measurable disease, there were three complete and nine partial responses for a measurable disease response rate of 50% (12 of 24 patients; 95% confidence interval [CI], 27% to 73%). In the 44 patients in whom pretreatment prostate-specific antigen (PSA) was elevated, 30 (68%) had a 50% or greater decrease, and 25 (57%) had a 75% or greater decrease in PSA. The combined measurable disease and biochemical response rate in all 46 assessable patients was 54% (three complete responses, 22 partial responses, 95% CI, 37% to 71%). The predominant toxicity was neutropenia, with 26% of patients having grade 3 and 30% having grade 4 granulocytopenia; there were no episodes of febrile neutropenia. Other common but mild adverse effects included malaise/fatigue, peripheral edema, and hyperglycemia. The incidence of thromboembolic events during therapy was 9%. With a median follow-up of 17 months, the median survival was 20 months. The median time to disease progression was 8 months for all patients, and 10 months for those with measurable disease.

CONCLUSION: This therapy is efficacious and moderately well tolerated in HRPC and should be compared in a phase III trial with mitoxantrone and prednisone.
BRCA1/2 Testing: Complex Themes in Result Interpretation
Authors: Peshkin Beth N. , DeMarco Tiffani A. , Brogan Barbara M. , Lerman Caryn , Isaacs Claudine
Published: February 2017

ABSTRACT: Since the cloning of BRCA1 and BRCA2, genetic testing for breast and ovarian cancer susceptibility has become more widespread. However, interpretation of test results is not always straightforward. To illustrate this point, five vignettes adapted from actual cases are presented. As these cases demonstrate, in many high-risk families, a deleterious mutation in BRCA1 or BRCA2 is not identified in an affected proband. There are several potential explanations for such a finding, namely that an undetected mutation in BRCA1 or BRCA2 may exist, or there could be a mutation in a rare or undiscovered gene. In addition, the possibility that women with breast cancer represent sporadic cases within hereditary cancer families must also be considered. Finally, the occurrence of BRCA1/2 variants of uncertain significance, often missense mutations, further complicates the risk assessment. In some of these instances, extending testing to relatives can be helpful to clarify results. When hereditary breast cancer cannot be ruled out, individuals may still be at increased risk for cancer and therefore need to obtain appropriate surveillance. The process of genetic counseling is critical both before and after testing to ensure that patients understand the potential medical and psychosocial implications of testing and are aware of available options and resources. A multidisciplinary approach to service delivery, which includes clinicians in genetics and oncology, can facilitate patients’ decision making and provide continued access to information and support.
Matrix Metalloproteinase Inhibitor COL-3 in the Treatment of AIDS-Related Kaposi’s Sarcoma: A Phase I AIDS Malignancy Consortium Study
Authors: Cianfrocca Mary , Cooley Timothy P. , Lee Jeannette Y. , Rudek Michelle A. , Scadden David T. , Ratner Lee , Pluda James M. , Figg William D. , Krown Susan E. , Dezube Bruce J.
Published: February 2017

PURPOSE: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and are overexpressed in Kaposi’s sarcoma (KS) cells. The primary aim was to define the safety and toxicity of the MMP inhibitor COL-3 in patients with AIDS-related KS. Secondary aims were to evaluate tumor response, pharmacokinetics, and changes in blood levels of MMP-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF).

PATIENTS AND METHODS: COL-3 was administered orally once daily, and doses were escalated in cohorts of three to six subjects. Patients with symptomatic visceral KS or severe tumor-associated edema were excluded. Antiretroviral therapy was permitted but not required. Study end points were grade 3 or 4 toxicity or progressive KS. Serial blood specimens were obtained for pharmacokinetics and levels of MMP-2, MMP-9, VEGF, and bFGF.

RESULTS: Eighteen patients received COL-3 in dosing cohorts of 25, 50, and 70 mg/m2/d. Prior KS therapy was reported by 17 patients (94%). COL-3–related grade 3 or 4 adverse events were reported by six patients and included photosensitivity, rash, and headache. There was one complete response and seven partial responses, for an overall response rate of 44%, with a median response duration of 25+ weeks. The median COL-3 half-life was 39.3 hours (range, 4.1 to 251.1 hours). There was a significant difference between responders and nonresponders with respect to the change in MMP-2 serum levels from baseline to minimum value on treatment (P = .037).

CONCLUSION: COL-3 administered orally once daily to patients with AIDS-related KS is reasonably well tolerated. The most common adverse event was dose-related photosensitivity. Antitumor activity was noted. Further evaluation of COL-3 for the treatment of KS is warranted.
Patients’ Estimation of Overall Treatment Burden: Why Not Ask the Obvious?
Authors: Bernhard J. , Maibach R. , Thürlimann B. , Sessa C. , Aapro M. S.
Published: February 2017

PURPOSE: We investigated the clinical validity of patients’ estimation of overall treatment burden. This measure was expected to be responsive to the wide spectrum of reactions on treatment and thus less precise for specific effects.

PATIENTS AND METHODS: After the first chemotherapy within a randomized, double-blind trial of the prophylaxis for delayed emesis (SAKK 90/95), 249 patients documented nausea and vomiting daily for 6 days. Over the whole period, they estimated nausea/vomiting (N/V) burden and overall treatment burden by linear analog-self assessment (LASA) indicators and documented other side effects.

RESULTS: At day 6, the two burden indicators were moderately correlated (r = 0.58) in accordance with their different concepts. No, partial, or total control of delayed emesis (days 2 to 6) was reflected in a consistent pattern by both indicators, with a stronger and more significant effect (P < .001) on changes in N/V burden than overall treatment burden. In contrast, toxicity other than N/V, assessed independently by patients and physicians, was mainly associated with overall treatment burden. Patients who indicated at least one other side effect rated their overall burden substantially higher than those with no indication of other toxicity (P < .0001). Physician-rated toxicity had a similar effect (P < .0001).

CONCLUSION: A direct patient estimation of overall treatment burden by a LASA indicator may serve as an end point in clinical trials, particularly when treatments with different toxicity profiles are being compared. It is complementary to physicians’ ratings of specific toxicities and a major component of patient-rated symptom checklists and quality-of-life measures.
Prospective Study of 90 Children Requiring Treatment for Juvenile Myelomonocytic Leukemia or Myelodysplastic Syndrome: A Report From the Children’s Cancer Group
Authors: Woods William G. , Barnard Dorothy R. , Alonzo Todd A. , Buckley Jonathan D. , Kobrinsky Nathan , Arthur Diane C. , Sanders Jean , Neudorf Steven , Gold Stuart , Lange Beverly J.
Published: February 2017

PURPOSE: We report the first large prospective study of children with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Children’s Cancer Group protocol 2891.

PATIENTS AND METHODS: Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (AML) with antecedent MDS were treated with a five-drug induction regimen (standard or intensive timing). Patients achieving remission were allocated to allogeneic bone marrow transplantation (BMT) if a matched family donor was available. All other patients were randomized between autologous BMT and aggressive nonmyeloablative chemotherapy. Results were compared with patients with de novo AML.

RESULTS: Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58% and 48%, respectively. Remission rates for patients with RAEB in transformation (RAEB-T) (69%) or antecedent MDS (81%) were similar to de novo AML (77%). Actuarial survival rates at 6 years were as follows: JMML, 31% ± 26%; RA and RAEB, 29% ± 16%; RAEB-T, 30% ± 18%; antecedent MDS, 50% ± 25%; and de novo AML, 45% ± 3%. For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy. The presence of monosomy 7 had no additional adverse effect on MDS and JMML.

CONCLUSION: Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes. Children with a history of MDS who present with AML do well with AML-type therapy. Patients with RA or RAEB respond poorly to AML induction therapy. The optimum treatment for JMML remains unknown.
Can Communication Skills Training Alter Physicians’ Beliefs and Behavior in Clinics?
Authors: Jenkins Valerie , Fallowfield Lesley
Published: February 2017

PURPOSE: To measure the psychosocial attitudes and beliefs of physicians working within oncology in the United Kingdom and to examine whether beliefs alter after communication skills training. Additionally, to investigate whether physicians’ attitudes are reflected in communication behaviors with patients during interviews.

METHODS: Ninety-three physicians completed a 32-item Physician Psychosocial Belief (PPSB) questionnaire at baseline (T1) before randomization to attendance at a 3-day residential communication skills course (n = 48) or a control group (n = 45). Three months later (T2), both groups completed another PPSB and a self-assessment questionnaire recording perceived changes in communication with patients. At both time points, physicians’ consultations with two consenting patients were videotaped. Communication behaviors were measured using the Medical Interaction Processing System.

RESULTS: Physicians who attended the course showed significantly improved attitudes and beliefs toward psychosocial issues compared with controls (P = .002). This improvement was reflected in the analysis of the videotaped recordings of their communication behaviors with patients. Expressions of empathy were more likely for the course group at T2 than the controls (P = .02), as were open questions (P = .001), appropriate responses to patient cues (P = .005), and psychosocial probing (P = .041). These objective findings were supported by physicians’ self report of changes in communication style during interviews with patients.

CONCLUSION: Our results show that a communication skills training intervention using behavioral, cognitive, and affective components not only increases potentially beneficial and more effective interviewing styles but can also alter attitudes and beliefs, thus increasing the likelihood that such skills will be used in the clinical setting.
Phase I Trial of Intraperitoneal Injection of the E1B-55-kd-Gene–Deleted Adenovirus ONYX-015 (dl1520) Given on Days 1 Through 5 Every 3 Weeks in Patients With Recurrent/Refractory Epithelial Ovarian Cancer
Authors: Vasey P. A. , Shulman L. N. , Campos S. , Davis J. , Gore M. , Johnston S. , Kirn D. H. , O’Neill V. , Siddiqui N. , Seiden M. V. , Kaye S. B.
Published: February 2017

PURPOSE: Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts.

PATIENTS AND METHODS: We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 × 109 plaque forming units (pfu), 1 × 1010 pfu, 3 × 1010 pfu, and 1 × 1011 pfu.

RESULTS: The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 × 1010 pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 1011 pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication.

CONCLUSION: This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.
DNA Microarrays in Clinical Oncology
Authors: Ramaswamy Sridhar , Golub Todd R.
Published: February 2017

ABSTRACT: Aberrant gene expression is critical for tumor initiation and progression. However, we lack a comprehensive understanding of all genes that are aberrantly expressed in human cancer. Recently, DNA microarrays have been used to obtain global views of human cancer gene expression and to identify genetic markers that might be important for diagnosis and therapy. We review clinical applications of these novel tools, discuss some important recent studies, identify promising avenues of research in this emerging field of study, and discuss the likely impact that expression profiling will have on clinical oncology.
Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane.
Authors: Blackwell Kimberly L. , Miles David , Gianni Luca , Krop Ian E. , Welslau Manfred , Baselga José , Pegram Mark D. , Oh Do-Youn , Dieras Veronique , Olsen Steven R. , Fang Liang , Lu Michael W. , Guardino Ellie , Verma Sunil
Published: February 2017

LBA1

Background: T-DM1 is an antibody-drug conjugate comprising T, a stable linker, and the potent cytotoxic agent DM1; it incorporates the antitumor activities of T and the HER2-targeted delivery of DM1. Methods: EMILIA is a randomized study of T-DM1 vs XL, the only approved combination for T-refractory HER2+ MBC. Patients (pts) received T-DM1 (3.6 mg/kg IV q3w) or X (1000 mg/m2 PO bid, days 1–14 q3w) + L (1,250 mg PO daily) until progressive disease (PD) or unmanageable toxicity. Pts had confirmed HER2+ MBC (IHC3+ and/or FISH+), and prior therapy with T and a taxane. Primary end points were PFS by independent review, OS and safety. An interim OS analysis (efficacy boundary: HR= 0.617; p=0.0003) was planned at the time of the final PFS analysis. Results: 991 pts were enrolled; 978 received treatment. Median (med) durations of follow-up were 12.9 (T-DM1) and 12.4 (XL) months (mo). Baseline demographics, prior therapy and disease characteristics were balanced. There was a significant improvement in PFS favoring T-DM1 (med 9.6 vs 6.4 mo; HR=0.650 [95% CI, 0.549–0.771]; p <0.0001). The med T-DM1 OS was not reached vs 23.3 mo (HR=0.621 [95% CI, 0.475–0.813]; p=0.0005); the interim efficacy boundary was not crossed. T-DM1 was well tolerated with no unexpected safety signals. The most common grade ≥3 adverse events (AEs) per treatment were for T-DM1: thrombocytopenia (12.9% vs 0.2%), increased AST (4.3% vs 0.8%), and increased ALT (2.9% vs 1.4%); for XL: diarrhea (20.7% vs 1.6%), palmar plantar erythrodysesthesia (16.4% vs 0) and vomiting (4.5% vs 0.8%). The table lists other end points. Conclusions: T-DM1 conferred a significant and clinically meaningful improvement in PFS compared with XL. Other end points support T-DM1 as an active and well-tolerated novel therapy for HER2+ advanced BC. [Table: see text]
Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.
Authors: Demetri George D. , Reichardt Peter , Kang Yoon-Koo , Blay Jean-Yves , Joensuu Heikki , Maki Robert G. , Rutkowski Piotr , Hohenberger Peter , Gelderblom Hans , Leahy Michael Gordon , von Mehren Margaret , Schoffski Patrick , Blackstein Martin E. , Le Cesne Axel , Badalamenti Giuseppe , Xu Jian-Ming , Nishida Toshirou , Laurent Dirk , Kuss Iris , Casali Paolo Giovanni ,   on behalf of GRID Investigators
Published: February 2017

LBA10008

Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG. Results: Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p<0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common > grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). Conclusions: This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.
Open-label phase III randomized controlled trial comparing taxane-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+ metastatic breast cancer: Interim analysis (IA) of NCIC CTG MA.31/GSK EGF 108919.
Authors: Gelmon Karen A. , Boyle Frances , Kaufman Bella , Huntsman David , Manikhas Alexey , Di Leo Angelo , Martin Miguel , Schwartzberg Lee Steven , Dent Susan Faye , Ellard Susan , Tonkin Katia Sonia , Nagarwala Yasir M. , Pritchard Kathleen I. , Whelan Timothy Joseph , Nomikos Dora , Chapman Judy-Anne W. , Parulekar Wendy
Published: February 2017

LBA671

Background: The relative efficacy of L vs T when combined with Tax chemotherapy in the first-line setting of metastatic breast cancer (BC) is unknown. Methods: MA.31 compares Tax-based therapy, paclitaxel 80mg/m2 wkly or docetaxel 75mg/m2 3 wkly for 24 wks in combination with L or T. The L dose was 1,250 mg po daily with Tax followed by 1,500 mg daily (LTax/L). After a loading dose, the T dose was 2 mg/kg wkly or 6 mg/kg 3 wkly + Tax followed by T 6 mg/kg 3 wkly (TTax/T). Stratification was by prior neo/adjuvant HER2 therapy, prior neo/adjuvant Tax, planned Tax (paclitaxel vs docetaxel), and liver metastases. The primary endpoint is ITT progression-free survival (PFS), defined as time from randomization to objective progressive disease based on RECIST criteria or death from any cause. The protocol-specified IA was performed after observing 333 PFS events; the trial was to stop if the 2-sided p-value from the stratified log-rank test was less than 0.03. The NCIC CTG’s independent DSMC reviewed IA results and recommended disclosure because the superiority boundary was crossed. A secondary analysis utilized central laboratory-confirmed HER2 + status. Results: Between July 17 2008 and Dec 1 2011, 652 pts were accrued. Data from 636 pts (525 HER2 centrally confirmed) were included in the IA with clinical cutoff date of Nov 7 2011 and database lock of Apr 13 2012. Median follow-up was 13.6 mos, 12.9 mos for LTax/L pts and 14.0 mos for TTax/T patients. In the ITT analysis, PFS was inferior with LTax/L compared to TTax/T hazard ratio (HR) =1.33; 95% CI 1.06-1.67; p=0.01. LTax/L had median PFS 8.8 mos (95% CI 8.3-10.6) compared to TTax/T 11.4 mos (95% CI 10.8-13.7). PFS in the centrally confirmed HER2+ had HR 1.48 (95%CI 1.15-1.92; p=0.003) (LTax/L to TTax/T). No difference in overall survival was detected (LTax/L to TTax/T) HR= 1.1 (95% CI 0.75-1.61; p=0.62). More grade 3-4 diarrhea and rash was observed with LTax/L (p<0.001). Conclusions: LTax/L therapy is associated with a shorter PFS compared to TTax/T as first line therapy for HER2+ metastatic BC. ClinicalTrials.gov: NCT00667251. CCSRI grant: 021039. Supported by GlaxoSmithKline.
LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations.
Authors: Yang James Chih-Hsin , Schuler Martin H. , Yamamoto Nobuyuki , O'Byrne Kenneth John , Hirsh Vera , Mok Tony , Geater Sarayut Lucien , Orlov Sergey V , Tsai Chun-Ming , Boyer Michael J. , Su Wu-Chou , Bennouna Jaafar , Kato Terufumi , Gorbunova Vera , Lee Ki Hyeong , Shah Riyaz N.H. , Massey Dan , Lorence Robert M. , Shahidi Mehdi , Sequist Lecia V.
Published: February 2017

LBA7500

Background: Afatinib (A) is a selective, orally bioavailable, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and ErbB4. This global study investigated the efficacy and safety of A compared with pemetrexed/cisplatin (PC) in pts with EGFR mutation positive advanced lung adenocarcinoma. Methods: Following central testing for EGFR mutations (companion diagnostic TheraScreen EGFR RGQ PCR kit), 345 pts (stage IIIB/IV, PS 0–1, chemo-naive) were randomized 2:1 (A: 230; PC: 115) to daily A 40 mg or iv PC (500 mg/m2 + 75 mg/m2 q21 days up to 6 cycles). Primary endpoint was progression-free survival (PFS) by central independent review. Results: Baseline characteristics were balanced in both arms: median age, 61 y; female, 65%; Asian, 72%; never-smoker, 68%; Del19, 49%; L858R, 40%; other mutations, 11%. Treatment with A led to a significantly prolonged PFS vs PC (median 11.1 vs 6.9 mos; HR 0.58 [0.43–0.78]; p=0.0004). In 308 pts with common mutations (Del19/L858R), median PFS was 13.6 vs 6.9 mos, respectively (HR=0.47 [0.34–0.65]; p<0.0001). Objective response rate was significantly higher with A (56% vs 23%; p<0.0001). Significant delay in time to deterioration of cancer-related symptoms of cough (HR=0.60, p=0.0072) and dyspnea (HR=0.68, p=0.0145) was seen with A vs PC. Most common drug-related adverse events (AEs) were diarrhea (95%), rash (62%) and paronychia (57%) with A, and nausea (66%), decreased appetite (53%) and vomiting (42%) with PC. Drug-related AEs led to discontinuation in 8% (A; 1% due to diarrhea) and 12% of pts (PC). Conclusions: LUX-Lung 3 is the largest prospective trial in EGFR mutation positive lung cancer and the first study using pemetrexed/cisplatin as a comparator. Treatment with afatinib significantly prolonged PFS compared to PC, with significant improvements in secondary endpoints. AEs with afatinib were manageable, with a low discontinuation rate. With 4.2 mos PFS improvement in the overall population and 6.7 mos in pts with common mutations, afatinib is a clinically relevant first-line treatment option.
TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wild-type (wt) EGFR.
Authors: Garassino Marina Chiara , Martelli Olga , Bettini Anna , Floriani Irene , Copreni Elena , Lauricella Calogero , Ganzinelli Monica , Marabese Mirko , Broggini Massimo , Veronese Silvio , Gherardi Giorgio , Longo Flavia , Fabbri Maria Agnese , Tomirotti Maurizio , Alabiso Oscar , Sarobba Maria Giuseppa , Labianca Roberto , Marsoni Silvia , Farina Gabriella , Scanni Alberto
Published: February 2017

LBA7501

Background: While the benefit of EGFR tyrosine kinase inhibitors in the treatment of patients with NSCLC harboring EGFR mutations has been widely established, their value in treating patients with wt EGFR is still debated. To assess the role of erlotinib in these patients, we performed an independent multicenter phase III trial (Tarceva Italian Lung Optimization Trial [TAILOR] NCT00637910), comparing erlotinib to docetaxel in second line treatment, having overall (OS) and progression free survival (PFS) as principal and secondary endpoints, respectively. Methods: EGFR and KRAS mutational status were assessed by direct sequencing in all eligible patients; only patients with wt EGFR NSCLC (exons 19 and 21) at progression, and previously treated with a first line platinum-based regimen, were randomized to receive either erlotinib 150 mg daily or docetaxel 75 mg/m2 (3-weekly) or 35 mg/m2 (weekly) until disease progression or unacceptable toxicity occurred. To detect an hazard ratio of 0.67 (2-sided 5% significance level for the log-rank test and a power of 80%), 199 events were required for both OS and PFS evaluation. Results: On the planned analysis date (March 30, 2012), 221 patients had been randomized and 218 were evaluable (docetaxel 110, erlotinib 108; three major violations excluded). At a median follow-up of 20 months, 199 relapses and 157 deaths were recorded. The Kaplan-Meier PFS curves showed a highly significant increase favoring docetaxel (HR 0.70 with 95% CI 0.53-0.94; p = 0.016) over erlotinib regimen. The HR translated into an estimated absolute difference in 6-months PFS of 12% (16% vs 28%). Data concerning toxicity were consistent with the literature. Conclusions: In terms of PFS, our results indicate a clear superiority of docetaxel over erlotinib as second line treatment for patients without EGFR mutations in exons 19 or 21. Analysis of OS will be conducted as far as the planned number of 199 deaths is reached.
Nomogram to predict sentinel lymph node involvement in patients with clinically node-negative breast cancer receiving neoadjuvant chemotherapy.
Authors: Allen Lisa R. , Gadgil Pranjali V. , Bassett Roland , Hunt Kelly , Mittendorf Elizabeth Ann , Yi Min , Babiera Gildy , Kuerer Henry Mark , Ross Merrick I. , Bedrosian Isabelle , Meric-Bernstam Funda , Hwang Rosa F.
Published: February 2017

150

Background: Sentinel lymph node biopsy (SLNB) has been shown to be an accurate predictor of axillary lymph node involvement in breast cancer patients treated with neoadjuvant chemotherapy (NAC). A predictive model of SLN positivity in clinically node negative patients who completed NAC can assist in preoperative multidisciplinary treatment decision making, such as planning for postmastectomy radiation therapy and breast reconstruction. Methods: We reviewed our prospective database to identifyclinically node negative patients with invasive breast cancer who underwent NAC and SLNB from 1998-2011. Clincopathologic factors including age, tumor location, histology, nuclear grade, tumor size, decrease in tumor size with therapy, multifocality, nodal appearance on preoperative ultrasound, hormone receptor status, and lymphovascular invasion (LVI) were analyzed. A nomogram to predict SLN metastasis was developed using multivariate logistic regression analysis. Results: A total of 836 patients were treated with NAC followed by SLNB. Of these, 160 patients (19.1%) had a positive SLN. All factors were significant predictors of SLN positivity on univariate analysis except tumor location and nodal appearance on preoperative ultrasound. Multivariate analysis showed that young age, invasive lobular histology, tumor size, multifocality, and LVI were independent positive predictors of SLN positivity whereas high grade, response to chemotherapy, and triple negative hormone receptor status were negative predictors. Favorable histologies were strongly associated with a lower rate of SLN positivity but were excluded from the nomogram due to small numbers of patients (N=14). Discrimination of the nomogram to correctly predict SLN positivity was measured using the area under the receiver operating characteristic curve (AUC). The unadjusted AUC was 75.9, while the internally validated 2000 bootstrap sample-adjusted AUC was 74.2. Conclusions: Neoadjuvant chemotherapy is known to decrease the incidence of positive nodes in breast cancer patients. Use of our nomogram preoperatively can assist in decisions regarding multidisciplinary treatment planning.
Tumor characteristics in obese women with breast cancer.
Authors: Chun Jennifer , Refinetti Ana Paula , Schnabel Freya Ruth , Price Alison , Billig Jessica , Cimeno Arielle , Schwartz Shira , Guth Amber , Axelrod Deborah M. ,   The Breast Surgery Section of NYULMC
Published: February 2017

179

Background: Obesity is an established risk factor for postmenopausal breast cancer. Though women with high BMI tend to develop less aggressive molecular subtypes, previous studies have shown that they still have a higher risk of recurrence and worse prognosis. The biological mechanisms for this difference in outcome have yet to be identified. The purpose of this study is to determine the correlation between obesity and tumor characteristics, including Ki67, and Oncotype DX scores in both pre- and post-menopausal women. Methods: The Breast Cancer Database of NYU Langone Medical Center was queried for patients who were newly diagnosed with invasive breast cancer. We looked at the following variables: menopausal status, body mass index (BMI), histology, stage, ER/PR/Her2-neu status, Ki67, and Oncotype DX scores. Obesity was defined as having a BMI (kg/m2) ≥30. We looked at Ki67 as a continuous variable. Oncotype scores were categorized as low (<18), intermediate (18-30), and high (>31). Statistical analyses were performed using Spearman Correlation Coefficients. Results: Out of a total of 648 patients with a median age of 59 years, 153 (24%) women had a BMI≥30. The majority of the obese women had stage I and II (88%) cancers that were ER positive (84%), PR positive (74%), Her2-neu negative (86%), with mean Ki67 of 22%, and low to intermediate Oncotype DX scores (85%). However, when compared with women of BMI <30, there was no correlation between BMI and tumor characteristics, even when stratified by menopausal status. Conclusions: In our cohort, obesity was not correlated with tumor stage, histology, Ki67 and Oncotype DX scores, even after adjusting for menopausal status. There are other factors that may explain the higher risk of recurrence and worse prognosis of breast cancer in obese women, such as insulin resistance, and obesity-related inflammatory cytokines that are independent of breast cancer subtypes and genomics. Treatment-related factors, such as non-compliance and inadequate dosing of chemotherapeutic agents, may also play a role in the worse outcome seen in this population. Further studies are necessary to identify measurable molecular characteristics of breast cancer in obese women that would allow us to predict more aggressive disease.
Factors influencing risk reduction surgery among BRCA mutation carriers: A qualitative analysis.
Authors: Brandt Rachael , Polinsky Cristina , Katz Jessica , Dhamankar Minal , Tucci Rosemarie , Sabol Jennifer L. , McHugh Terri
Published: February 2017

53

Background: Women known to carry deleterious mutations in BRCA1 and BRCA2 have a substantially increased lifetime risk to develop breast and ovarian cancer. Current risk management options include increased surveillance, chemoprevention and risk reducing surgery. Several studies have quantitatively evaluated the reasoning of high risk women for electing surgical intervention, noting mutation carrier status as a significant, but not sole rationale for this decision. The decision for surgery has also been associated with family cancer history, anxiety, demographics, healthcare setting and prior counseling. More insights regarding factors influencing women’s choice for risk reduction are needed. Methods: To further assess factors influencing the decision to have risk reduction surgery among women in a community hospital system, 129 BRCA mutation carriers in a community-based genetic counseling program were invited to participate in a qualitative study using questionnaires. A thematic analysis was performed by two independent reviewers on open dialogue responses. Results: Of the 59 respondents, 54 completed the question specifically addressing factors regarding the decision on surgery. Of them, 32 opted for mastectomy, salpingo-oophorectomy or both and 22 opted against surgical risk reduction. Themes emerging in support of surgery included: vicarious experience attributable to a strong family history of cancer; desire for control over risk through surgical intervention; high risk perception; co-morbidities; desire for living, regarding longevity and for loved ones; fear of cancer; and skepticism related to cancer detection methods. For women opting against surgery, themes included: co-morbidities; age (too old/young); incomplete childbearing; logistics (scheduling, finances); lack of disease; and skepticism in effectiveness of surgery. Conclusions: While various factors have been studied regarding the association with or probability of women’s decisions for risk reduction surgery, a deeper comprehension of women’s reasoning can be attained through qualitative analysis. This understanding may enhance health care providers’ ability to counsel women regarding this choice.