bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome of phase II oncology clinical trial abstracts presented at annual meeting of the American Society of Clinical Oncology (ASCO)
Authors: Hoeg R. T. , Lee J. A. , Mathiason M. A. , Rokkones K. , Serck S. L. , Crampton K. L. , Emmel A. , Jumonville A. J. , Severson E. A. , Go R. S.
Published: March 2020

6010

Background: Translation of evidence-based medicine into clinical practice depends on timely and full publication of clinical trials. Previous studies have shown that a substantial number of phase I and III trials presented at the annual meetings of ASCO remain unpublished more than 5 years after presentation. We investigated the outcome of phase II trials presented at ASCO. Methods: We searched for phase II trials using the 1997 ASCO Annual Meeting Proceedings. We excluded trials reporting only preliminary data or interim analyses. The following information were extracted from each study: type of presentation, country of origin, sample size, sponsor, treatment modality, novelty of treatment, and efficacy. A literature search was performed using the Medline and EMBASE databases up until January 2006 for full publications in peer-reviewed journals. If a trial was not found, the authors were contacted by E-mail. Results: We identified 124 phase II trials with 13.7%, 30.6%, and 55.6% presented orally, in poster, and in print, respectively. Most trials were either submitted from countries in North America (50.8%) or Europe (34.7%). Funding came from the pharmaceutical companies (24.2%), governments (20.2%), study institutions (15.3%), private foundations (9.7%), or was not specified (30.6%). The top 5 cancers studied were lung, breast, ovarian, gastric, and sarcoma. Treatment included mostly chemotherapy, either alone (87.1%) or in combination with other modalities (3.2%). To date only 70.2% of the trials have been published. The median time to publication for all abstracts was 23 months. The cumulative rates of publication were 12.9%, 34.7%, 51.6%, 64.5%, and 68.5% at 1, 2, 3, 5, and 7 years, respectively. None of the factors we analyzed, including type of presentation, country of origin, sample size, sponsor, novelty of treatment, and efficacy, influenced the likelihood of or time to publication. Conclusions: About a third of phase II oncology clinical trials initially presented as abstracts at the 1997 ASCO annual meeting have not been published almost a decade later. Similar to phase I and III trials, underreporting of phase II trials is an important problem with serious implications for clinical practice that needs to be addressed.

No significant financial relationships to disclose.
Defining significant adverse events (AEs) in advanced colorectal cancer (Adv CRC) patients in the community oncology practice setting
Authors: Kwan P. G. , Koeller J. M. , Simon J. , McKibbin T.
Published: March 2020

6017

Background: In contrast to clinical trials, standard (ie WHO) AE criteria are rarely used in community practice (CP). Because focusing on clinical decisions has more utility, we define a clinically significant (sig) AE as one resulting in deviation from planned chemo delivery. AEs are broadly categorized as tox resulting in a regimen change, a dose decrease, a delay, or an extra visit/hospitalization. Methods: Retrospective study. From 7/05–12/05 a team of oncology RPhs went on-site to 4 large US clinics (OH, NV, ME, FL), capturing all available Adv CRC pts receiving chemo. Pt, regimen, line of therapy, drug, cycle (cy), treatment (tx), toxicity (tox), and delay information were recorded. Delays were categorized as admin/other delays or tox-related delays. Pts who expired before 1/1/03 were excluded. Results: 207 pts (74 expired) received 2,444 cycles (79% from ‘04–05) Avg age = 65 years, 50% male and median ECOG PS = 1. Median survival = 17 mo. Six hundred two sig AEs (24.6% of cycles, combined endpt) were recorded (see Table ). The top regimens (cycles) were: 1st line - Folfox4 (427), IFL (259), Roswell Park (157), CapeOX (89), Folfox 6 (76), Cape Single Agent (73), Folfiri2 (62); 2nd line - Folfox4 (115), CPT11 Single Agent (96), CapeOX (71), IFL (60), Cape Single Agent (57), Roswell Pk (53), Folfiri2 (47). MoAb (cetuximab/bevacizumab) was added in 48% of regimen cycles. Of interest, single agent cpt11 (+MoAb in 80% of cy) is a common 2nd-line regimen. Two other references describe this regimen (Saltz Proc ASCO 2001; Cunningham NEJM 2004). Our data confirm this regimen’s tolerability. Conclusion: In the tx of Adv CRC, there is a wide variation in community oncologist prescribing patterns. We defined regimen tox based on criteria focusing on clinical decision making and showed the feasibility of measuring tox-related delays apart from other non-tox delays. Toxicity reported in this fashion may prove valuable for oncology administrators seeking to employ disease management strategies.

[Table: see text]

[Table: see text]
Predictive factors for the underutilization of adjuvant chemotherapy in colon cancer in Southwestern Sydney
Authors: Ng W. L. , Gabriel G. , Moylan E.
Published: March 2020

6070

Background: Adjuvant chemotherapy improves survival in stage III and high risk stage II colon cancers and is therefore recommended in current treatment guidelines. Despite this, retrospective studies demonstrate that utilization rates remain suboptimal in Australia and other countries. In this study we aimed to identify predictive factors for adjuvant chemotherapy underutilization in the Southwestern Sydney Area Health Service (SWSAHS). Methods: We examined data collected on all patients with a diagnosis of stage II or III colon and rectosigmoid cancers from SWSAHS colorectal database between 1997 and 2003. Follow-up and survival were calculated until October 2005. SPSS was used for statistical analysis and Kaplan-Meier for survival analysis. Results: 704 patients were identified. The overall adjuvant chemotherapy utilization rate was 48% (68% for stage III and 26% for stage II). Overall 5 year survival was 69% for patients who received adjuvant chemotherapy compared with 39% for those who did not receive chemotherapy (p<0.001). The main predictive factor identified for not receiving chemotherapy in both stages was increasing age. Rates of utilization of adjuvant chemotherapy for stage III colon cancer were 90% (<50 yrs), 81% (50–69 yrs) and 50% (70+ yrs). The trend was similar for stage II patients with corresponding utilization rates of 69%, 37% and 10%, respectively. The difference in chemotherapy utilization by age groups is highly significant (p<0.001). Other factors including sex, health insurance status, site of primary colon cancer and index of relative socioeconomic disadvantage did not show significant difference in chemotherapy usage. We were unable to evaluate the effect of co-morbidity on chemotherapy use from our database. Conclusions: Increasing age is the single most important predictive factor in the underutilization of adjuvant chemotherapy in colon cancer despite evidence that the elderly can accrue the same benefit from adjuvant chemotherapy as their younger counterparts.

No significant financial relationships to disclose.
Bupropion in the tratment of sexual dysfunction in women diagnosed with breast cancer: An open-label, fixed dose study
Authors: Mathias C. , Moraes E. , Bastos C. , Athanazio R. , Nunez G. , Alban L. , Braghirolli I. , Del Giglio A. , Pondé E. , Moore H.
Published: March 2020

6072

Background: Sexual morbidity after chemotherapy and hormonal therapy for breast cancer can seriously affect patients’ quality of life. Bupropion is an antidepressant that has been reported to increase libido. Objective: To investigate the improvement of sexual function in female breast cancer patients using bupropion. Methods: We performed an eight week open trial using bupropion in women diagnosed with breast cancer who had received chemotherapy and were currently receiving adjunctive hormonal therapy. The Arizona Sexual Experience Scale (ASEX) was used. The ASEX scale includes five questions that evaluate sexual function in the following areas: libido, excitability and ability to reach orgasm. Women received oral Bupropion 150mg/ daily for eight weeks and were evaluated prior to the initiation of the study and again during Weeks 4 and 8. Results: Twenty patients were included in the study. At the beginning of the study, the mean ASEX score was 23.45 [21.67–25.24] 95% CI. After four weeks of treatment, we observed a reduction in the mean ASEX score that persisted until the end of the study, at eight weeks: 18.45 [16.59–20.31] 95% CI, p = 0.0003) and 18.95 (SD ± 5.02 [16.60–21.30] 95% CI, p = 0.0024), respectively. Conclusions: In this non-controlled open trial bupropion 150 mg/daily was associated with improved sexual function in women receiving adjuvant systemic treatment for breast cancer.

No significant financial relationships to disclose.
Conventional cautions regarding online information: Do they predict accuracy of breast cancer websites?
Authors: Meric-Bernstam F. , Walji M. , Sagaram D. , Sagaram S. , Johnson C. W. , Bernstam E V.
Published: March 2020

6086

Introduction: Cancer patients and oncologists are increasingly using the Internet. Online information is affecting patient decisions regarding treatment. Therefore, multiple organizations published advice on how to screen out problematic information online. In the present study, we sought to determine whether existing quality assessment tools can screen out false or inaccurate breast cancer information online. Methods: Using 15 representative search queries on five popular search engines and only the first page of results, we generated a list of 1,585 Web pages. After eliminating irrelevant, broken and duplicate links 343 unique web pages were downloaded and evaluated for website characteristics, information accuracy and 15 quality criteria: authorship identified, author credentials identified, physician credentials stated, author affiliation stated, sources clear, general disclosures, attribution/references provided, disclosure of ownership, date created displayed, date of last update displayed, date of creation or last updated displayed, editorial process stated, internal search engine present, feedback mechanism provided and copyright notice. Quality criteria were evaluated by an independent evaluator blinded to the accuracy information. Accuracy was determined independently by a pair of clinically trained evaluators. Results: Of 343 pages evaluated, 41 false/misleading statements were displayed on 18 distinct pages. The presence of an internal search engine was correlated most strongly (r = .196, r2 = .038) with health information accuracy. However, all quality criteria (alone or in combinations tested exhaustively) were linearly associated with less than 7% of the variance in number of inaccuracies per website. Conclusion: Currently available technical quality criteria do not identify false or misleading online information about breast cancer. At this time, directing patients to websites with known content appears to be the only way to ensure patients will not encounter false or misleading online information.

No significant financial relationships to disclose.
Method of detection of local recurrence in patients following breast conserving surgery and its utility for surveillance
Authors: Taback B. , Hansen N. , Conway K. , Giuliano A.
Published: March 2020

611

Background: It is estimated that approximately 10% of all breast cancer patients will develop local recurrence (LR) at 10 years. Routine surveillance for detection of early breast cancer recurrence is widely performed despite lack of conclusive evidence for an improvement in patient quality of life or potential for cure. A number of historical studies evaluating the effectiveness of routine screening for LR following treatment for early-stage breast cancer have suggested that the diagnosis of LR is more frequent during a routine visit and occurring in asymptomatic patients. However, differentiating the method of detection is not often elucidated. In this study we evaluated the manner in which patients presented with an isolated LR in clinical practice. Methods: Our routine patient follow-up consists of physical exam and mammogram every 6 mos for the first 2 years following breast conserving surgery (BCS) and yearly thereafter. We queried our prospectively collected breast cancer database (1632 patients from July 1986 - July 2004) for patients with an isolated LR following BCS (n=59 (3.6%); two patients had bilateral LRs). Medical records were not available for three patients. Results: At a median follow-up of 45 mos (range: 5–122 mos) there were 58 evaluable LRs: 15 DCIS, 31 infiltrating ductal carcinoma (IDC), 6 infiltrating lobular (ILC), 2 mixed IDC/ILC, 3 invasive cancers NOS and 1 unknown. Patient presentation was as follows: 25 were diagnosed by self-exam, 28 on screening mammogram, 2 were diagnosed by physician (includes one referral), and 3 unknown. Mammogram detected recurrences were more frequent among patients with DCIS whereas self-detected recurrences were more common in patients with IDC (79% vs 33% and 21% vs 67%, respectively; P<0.2). Mean tumor size was larger in self-presentation (2.1 cm; range: 0.8–4.5 cm) than in mammogram detected group (1.6 cm; range 0.4–6 cm). Conclusions: These findings demonstrate the value of mammography as compared to patient detected LRs. Whether a survival advantage exists remains uncertain. Nevertheless routine physician examination in this setting is highly insensitive and its further utility must be considered when devising cost-effective strategies for surveillance of breast cancer patients.

No significant financial relationships to disclose.
Does ovarian cancer survival differ by who gives the chemotherapy?
Authors: Silber J. H. , Rosenbaum P. R. , Polsky D. , Ross R. N. , Schwartz J. S. , Even-Shoshan O. , Armstrong K. , Randall T. C.
Published: March 2020

6110

Background: Medical Oncologists (MOs) specialize in administering chemotherapy while Gynecologic Oncologists (GOs) specialize in the surgical management of gynecologic cancers as well as providing chemotherapy. We asked whether survival differed according to the type of specialist providing the chemotherapy after ovarian cancer surgery. Methods: Using merged SEER-Medicare clinical and administrative data from the years 1991 through 2001 we identified all patients who were diagnosed with ovarian cancer after the age of 65 and who received chemotherapy from a GO after surgery performed by any type of surgeon. Using optimal matching and a propensity score based on 35 prognostic characteristics, we identified similar patients who were operated on, and staged, by nearly identical types of surgeons but who received chemotherapy from an MO. Results: We identified 344 patients who were given chemotherapy for ovarian cancer by GOs after having undergone surgery by either GOs (76%), Gynecologists (16%), or general surgeons or other surgical specialties (8%). Patients given chemotherapy by MOs were matched to these patients. Both groups had nearly identical surgical specialists, age, year of treatment, stage, tumor grade, race and 32 other prognostic factors. There was no difference in overall survival between the GO or MO groups (P = 0.45, paired Prentice-Wilcoxon test). The 5 year survival was 35% (± 2.6%) for the GO group and 34% (± 2.6%) for the MO group. However, MOs administered chemotherapy over more weeks than did the GOs (patient mean = 16.5 Vs 12.1 weeks, P < 0.0023, Wilcoxon rank sum test) and MO patients had more weeks that included at least one of the following chemotherapy associated adverse events (neutropenia, anemia, thrombocytopenia, diarrhea, dehydration or mucositis) than did the GO group (patient mean = 16.2 Vs 8.9 weeks, P < 0.0001, Wilcoxon rank sum test). Conclusions: Despite differences in training, specialty emphasis, and practice style concerning the use of chemotherapy (MO patients had more weeks of chemotherapy and more weeks with chemotherapy associated adverse events than GO patients), we found no difference in survival between patients who received chemotherapy administered by gynecologic oncologists and medical oncologists.

No significant financial relationships to disclose.
Effect of follow-up provider source on outcomes of patients with hematologic malignancies receiving hematopoietic stem cell transplantation
Authors: Loberiza F. R. , Villanueva M. H. , Devetten M. , Ganti A. K. , Maness L. J. , Bierman P. J. , Bociek R. G. , Armitage J. O. , Vose J. M.
Published: March 2020

6112

Background: Studies have shown that involvement of trained physicians is associated with favorable outcomes of patients receiving hematopoietic stem cell transplantation (HSCT). At the University of Nebraska Medical Center (UNMC), most patients are shifted back to the care of their referring physicians in the first 100 days. We evaluated whether the practice of shifting care of patients from specialists to primary care providers (PCP), referred to as patient care oscillation, in HSCT results in optimal outcomes. Methods: Data from 666 patients who underwent HSCT for malignant hematologic disorders between 2000 and 2003 were analyzed. Cox proportional hazards regression analyses were done to compare the relative risk of relapse/progression and mortality at 100-days and 1-year between patients whose care remained with specialists (transplant MDs at UNMC or community oncologist) versus those who were transferred back to the care of referring PCPs while adjusting for patient and disease factors. Results: Rate of patient care oscillation varies according to type of transplant. In allo-HSCT, 50% of patients received follow-up care from PCPs, 30% from community oncologists, while 20% remain at UNMC for follow-up. In auto-HSCT, 70% of patients received follow-up care from PCPs, 20% from community oncologists, while 10% remain at UNMC for follow-up with transplanting physicians. Outcomes after HSCT according to type of transplant is shown in the table. Conclusions: These preliminary findings suggest that in both allogeneic and autologous HSCT, the risk of disease progression/relapse and mortality may be independent of the type of follow-up care provider. However, further studies are needed to determine whether the practice of shifting the care of HSCT patients results in similar medical care utilization, post-transplant complications, re-hospitalizations and patient satisfaction. Patients likely to benefit from specialized versus primary care should be identified.

[Table: see text]

No significant financial relationships to disclose.
Prescription compliance and persistency in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) patients (pts) on imatinib (IM)
Authors: Tsang J. , Rudychev I. , Pescatore S. L.
Published: March 2020

6119

Background: IM (Glivec, Gleevec) is an oral targeted therapy with unprecedented efficacy in CML and GIST. Prescription compliance and persistency of pts receiving IM were measured by analysis of pt-level pharmacy claims data. Methods: Compliance and persistency were determined by analyzing the prescription-filling activity of pts (N=4043) compared with the prescribing activity of their physicians (N=3316) using pt pharmacy records accrued over 24 months (1/03–12/04). Observed average daily consumption (DACON) and average prescribed days of therapy were calculated and compared. Also, compliance and persistency were examined by pt demographics and initial IM dose prescribed. Results: Overall compliance (defined as medication possession ratio = apparent mg taken/mg prescribed) was 75%, with CML pts showing slightly greater compliance (78%) than GIST pts (73%). Fifty percent of pts were 100% compliant, the greatest compliance being found in pts initially treated with IM 300 or 400 mg/day (77%). Persistency (time on therapy without significant gaps in refills) averaged 255 days over 24 months. The most persistent pts were those initially given 300 or 400 mg/day (13.0 and 12.9 months, respectively). DACON was 400 mg/day for 65% of patients, but fluctuated above and below 400 mg/day in 18% and 17% of pts, respectively. Conclusions: This is the first assessment of pt compliance and persistency with prescribed IM therapy. Although less pronounced than with most other non-oncology products, suboptimal compliance and persistency with IM are a concern as doses <300–400 mg may result in plasma levels lower than needed to eliminate cancer cells. Patient support programs and improved communication on the importance of adhering to recommended dosing could potentially optimize outcome and further reduce risk of relapse and progression.

[Table: see text]
Outcome of interventions to identify family history and risk management for women with breast cancer in the ambulatory setting
Authors: Washburn N. J. , Simmons S. , Sommer V. , Adkins B. , Gerken P. , Rogers M. , Wilson B. , Lang B. , Hickman B. , Barnhart C. , Ethirajan S.
Published: March 2020

6121

Background: In 2002, Kansas City Cancer Center (KCCC) performed a quality improvement (QI) project to evaluate how breast cancer patients were being assessed for family history and cancer risk management. A self-administered family history questionnaire was developed to improve the thoroughness of family history collected and education of clinicians was completed to improve the recognition of risk factors based on ASCO guidelines. Methods: Chart audits on 210 women with breast cancer at KCCC, were completed in the second quarter of 2005. All patients were under the age of 65, not undergoing chemotherapy. A risk management tool was developed. Scoring criteria for 2002 was replicated in 2005 as listed in the table . Results: In 2002, 171 pts (89%) had level 1 or 2 family history assessed compared to 207 pts (99%) in 2005, p<0.0001. In 2002, 47% had 3 generations assessed compared to 84% in 2005, p<0.0001. In 2002 and 2005, some risk factor management occurred in both groups, and was equal, 78% and 80% respectively (p=ns). Of those that had risk management 33% had level 1 in 2002 compared to 3% in 2005 (p<0.0001) a 91% reduction in identifying risk without subsequent management. In 2002, 58% had level 2, compared to 71% in 2005 (p=0.02) a 23% improvement in identification & management of risk. In 2002, 9% had level 3 compared to 26% in 2005 (p<0.0001) a 183% improvement in patients with a detailed risk assessment and/or genetic referral. Conclusions: By improving the assessment of family history and education of providers, women with breast cancer are receiving more information to reduce their risk for recurrence and complications. Patients who were identified as high risk for BRCA1 or BRCA2 mutations were referred to either a nurse practitioner or genetic counselor.

[Table: see text]

No significant financial relationships to disclose.
Aromatase inhibitor (AI)-associated arthralgia (A) and bone pain (BP): Frequency and characterization in clinical practice
Authors: Presant C. A. , Kelly C. , Bosserman L. , Upadhyaya G. , Vakil M. , Horns R. , Ebrahimi B. , Yeon C. , Howard F. , Rios A.
Published: March 2020

6137

Background: Prior studies of AI have identified A and/or BP as side effects. Reported incidences have varied from 4% (IMPACT) to 35.6% (ATAC). In order to determine the frequency of A or BP in clinical practice, we reviewed a consecutive series of patients (PTs) receiving AI in community cancer centers. Methods: The charts of consecutive PTs receiving AI were reviewed, and PTs were interviewed regarding the occurrence of A or BP (ABP), severity, whether ABP was worse than before AI therapy, preexisting co-morbidities, type of therapy for ABP, and pain characterization. Results: 56 PTs were receiving AI. The type of AI used was anastrazole in 44 PTs, letrozole in 10 PTs, and exemestane in 2 PTs. The age range was 45 to 89 years. All PTs had breast cancer. The duration AI usage was 1 to 44 mo. Worsening of ABP compared to pretreatment ABP was reported in 34 PTs (61%). In 11 Pts (20%), severity was sufficient and control poor enough to result in discontinuation of AI at a median of 2 mo of AI therapy. The median severity of ABP, when present, was 7.5 on a 10 point pain scale. The character of the ABP was continuous in 20 (59%) and intermittent in 14 (41%), affected central/axial bones in 20 (36%), and peripheral bones in 35 (64%). Coexisting conditions possibly contributing to worsening of ABP occurred in 36%, consisting of degenerative joint disease 10, fibromyalgia 1, osteoporosis 4, and degenerative disc disease 1. Therapy associated with amelioration of symptoms included acetaminophen in 26%, NSAIDs in 45%, mild opiates in 11%, strong opiates in 5%, and glucosamine in 13%. The occurrence of ABP was not associated with age (68% in PTs less than 60 versus 57% in PTs over 60). The occurrence of ABP was not associated with duration of use of AI (50% of 16 Pts on AI for 3–6 mo, 75% for 7–12 mo, and 56% for over 12 mo). Conclusions: The occurrence of AI associated ABP is higher in a non-clinical trial population of PTs than reported in most clinical trials. This side effect is severe enough to cause discontinuation of needed AI therapy in 20%. Further studies are warranted to determine the mechanism of AI associated ABP, and optimal therapy. It is reasonable to consider glucosamine as well as standard analgesics in controlling this syndrome.

No significant financial relationships to disclose.
Principal factor analysis of predictive markers of response and resistance to primary chemo-endocrine treatment in elderly breast cancer (BC) patients
Authors: Generali D. G. , Fox S. , Buffa F. M. , Berruti A. , Brizzi M. , Allevi G. , Bonardi S. , Dogliotti L. , Bottini A. , Harris A.
Published: March 2020

618

Background: This study was undertaken to identify protein expression patterns able to predict response and resistance to chemo-endocrine therapy in elderly BC patients enrolled in a randomised phase II study. Methods: 114 women with T2–4 N0–1, estrogen receptor positive BC were randomly assigned to 6 months of primary Letrozole (L) (2,5 mg/daily) or L plus oral “metronomic” cyclophosphamide (50 mg/daily) (LC). Expression of 24 markers was assessed before treatment on TMAs. Markers were involved in signalling and angiogenic/hypoxia pathways as follow; erbB2, T regulatory cells, caspase3, BNIP3, phosphorylated ERaplha, CCDN1, mTor, Hif-1α, phd1, phd2, phd3, CA9, COX2, p38, p44, EGFr, PI3k, pAkt, CD31, VEGF, Ki67, p53, bcl2, herb2. Principal factor (PF) analysis attempts to identify underlying factors that explain the correlation patterns within a set of observed variables; here, PF analysis was used to reduce the marker expression data by identifying a small number of PFs that explained most of the variance observed. These PFs were introduced in a multivariate logistic regression (MLR) to study basal protein expression profiles with response to chemo-endocrine treatment. Clinical variables such as treatment, age, tumor size, nodal status, grading and histotype were also included in MLR. Results: 91 out of 113 evaluable patients (80.5%) attained a disease response, 48 patients a complete response (CR) (42.5%) whereas 22 did not respond (19.5%). The first 12 extracted PFs from PF analysis explained 80% of the expression data variance; these were considered in a MLR together with clinical variables. The 4th PF, mainly representing Hif-1α and p44 expression, and at lower degree EGFr expression, was the only independent predictor of disease response (OD=0.22, p=0.003). The 6th PF, mainly representing phosphorylated ERalpha expression, was the only independent factor associated with CR (OD=2.036, p=0.023). There was no interaction between these PFs and treatment randomisation. Conclusion: The activated form of ERalpha is with complete response, whereas Hif-1α and p44 were able to discriminate patients resistant to chemo-endocrine treatment. In this latter cohort, specific target therapies can be recommended.

No significant financial relationships to disclose.
FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer
Authors: Thussbas C. , Nahrig J. , Streit S. , Bange J. , Kates R. , Ulm K. , Kiechle M. , Hoefler H. , Ullrich A. , Harbeck N.
Published: March 2020

625

Background: Bange et al. recently found that a single-nucleotide polymorphism (SNP) at codon 388 of fibroblast growth factor receptor 4 (FGFR4) gene, causing a transmembrane domain missense mutation (Gly388Arg), is associated with outcome in node-positive breast cancer. Methods: This study addresses clinical relevance of this SNP, FGFR4 genotype, phenotype, and HER2 regarding patient outcome and influence of adjuvant systemic therapy in a substantial primary breast cancer collective (n=372; 1987–2002), median follow-up 94.5 months. Treatment was administered according to consensus recommendations at the time: 73 patients (all N0) received no adjuvant systemic therapy; 114 received adjuvant chemotherapy (87% CMF-based), 164 tamoxifen, 10 combined chemo-endocrine therapy, 11 unknown. 128 (36%) patients experienced disease recurrence, 104 (81%) distant relapses; 140 (38%) died. PCR-RFLP-analysis of germ-line polymorphism was performed in uninvolved lymph nodes; FGFR4 and HER2 expression were assessed immunohistochemically in tumor tissue arrays. Primary endpoint was DFS, since it best reflects impact of adjuvant systemic therapy. Results: In 51% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between FGFR4 genotype and expression or HER2 status. In N0 patients, FGFR4 genotype was not correlated with disease outcome. In N+ patients, however, FGFR4 Arg388 was significantly associated with poor DFS (p=0.02) and OS (p=0.04). Notably, this association seems to be attributable to relatively poor therapy response in Arg388 carriers, reflected in their significantly shorter DFS (p=0.02) and OS (p=0.045) among patients receiving adjuvant systemic therapy. It is also seen as a significant interaction term in a multivariate proportional hazards model with Arg388 carriers having only about half as much benefit from adjuvant systemic therapy as wild-type carriers. Conclusions: Our results show that the previously found association of FGFR4 Arg388 genotype with breast cancer progression is strongest in patients with adjuvant systemic therapy, particularly chemotherapy, and thus may reflect therapy resistance.

No significant financial relationships to disclose.
Randomized phase II trial evaluating the efficacy of adding sequential half body irradiation (SHBI) to adjuvant chemotherapy in high-risk breast cancer patients with >10 positive lymph nodes
Authors: Barsoum M. S. , Gafar R. M. , Nazmy M. M. , Niazy A.
Published: March 2020

627

Background: Adjuvant sequential half body irradiation (SHBI) is both interesting as well as scientifically sound approach with proven efficacy in many tumors. Methods: Patients with node positive (≥10) breast cancer were randomized in this phase II trial to receive either 6 cycles of adjuvant cyclophosphamide 500 mg/m2, 5FU 500 mg/m2 and epirubicin 100 mg/m2 followed by postoperative local irradiation (Arm A) versus the same adjuvant treatment plus consolidation SHBI staring 3 weeks after end of adjuvant treatment with upper half 750cGy /5 fractions /1week then one month gap followed by the lower half for the same dose (Arm B) Results: Between November 1999 and November 2000 a total of 70 patients who met the eligibility criteria were enrolled. Arm A (n=35) and arm B (n=35) were almost comparable with the respect to different prognostic factors. There was significant improvement in the disease free survival (DFS) at 5 years in arm B. The DFS was 65±8% in arm B while it was 33±8% in arm A (log-rank test: P =0.0036). In subset analysis the difference is apparent in subgroups of patients with less potential metastatic burden, which are T2 cases and ER positive cases. The DFS at 5 years was 83% in arm B and it was 35% in arm A (P=0.0008) in T2 cases. In the subgroup of patients with ER positive tumors (n=51), the DFS at 4 years was 58% in arm B and it was 25% in arm A (P=0.0072). The complications of the addition of SHBI were mild (grades 2 and 3) and mainly gastrointestinal (vomiting, diarrhea and colic). In both arms of the study there were no life-threatening complications or treatment-related mortality. Conclusions: SHBI was found to be a well-tolerated consolidation regimen with acceptable side effects and it showed significant improvement of the DFS in breast cancer patients with ≥ 10 positive lymph nodes especially in the relative cases with good prognosis (T2-ER positive). This makes it worthy of testing in a phase III trial.

No significant financial relationships to disclose.
CYP2D6 genotypes in association with steady state plasma concentrations of active metabolites of tamoxifen in patients with breast cancer
Authors: Lim H. , Lee H. , Lee K. , Lee E. , Jang I. , Ro J.
Published: March 2020

634

Background: Tamoxifen is a prodrug that is metabolized to active metabolites, Z-4-hydroxy-N-desmethyltamoxifen (BX) and Z-4-hydroxy-tamoxifen (4OH) where CYP2D6 plays a major role in the conversion. Genetic polymorphisms of CYP2D6 by ethnicities are well known with CYP2D6*10 in Asians (up to 50% in Koreans), and CYP2D6 *2 and *4 in American Whites as major variant alleles. We analyzed the steady state plasma concentrations of tamoxifen and its metabolites in patients (pts) with breast cancer to evaluate their associations with various CYP2D6 genotypes. Methods: Blood samples were collected from 219 pts on tamoxifen, 20 mg daily as adjuvant therapy for more than 3 months at National Cancer Center, Korea. Plasma tamoxifen, N-desmethyltamoxifen, BX, 4OH were measured by validated HPLC with fluorescence detector, and analyzed according to CYP2D6 genotype groups by Wilcoxon rank sum test. CYP2D6*10, CYP2D6*5 and CYP2D6*2×2 were identified by PCR-RFLP methods, and the rests were classified as CYP2D6*1 (wild type). This study was approved by IRB at National Cancer Center Hospital (NCCNHS04–033) and conducted after informed consent obtained by the patients. Results: Thus far, we measured plasma concentration of tamoxifen and its metabolites for 158 pts among 198 pts genotyped. 59 pts (29.8%) carried CYP2D6*1/*1, 84 pts (42.4%) *1/*10 and 49 pts (24.7%) *10/*10. Other types were CYP2D6*1/*5 (8.6%), *5/*5 (1.0%), *1/*2×2 (2.5%). Pts with CYP2D6 *10/*10 (n=40) demonstrated significantly lower steady state plasma concentrations of BX and 4OH than those with other genotypes (n=118) (BX: 7.9 vs.19.2. ng/ml [95 % CI; 5.5–10.4 vs. 15.8–22.7 ng/ml] p<0.0001; 4OH: 1.5 vs. 2.8 ng/ml [95 % CI; 1.1–2.0 vs. 2.3–3.3 ng/ml] p<0.0001), whereas there were no differences with *1/*10 (n=64) vs. without *10 allele (n=54) (BX: 20.6 vs. 18.1 ng/ml; 4OH: 2.9 vs. 2.7 ng/ml). Basically no significant differences in BX/4OH or other compounds by various CYP2D6*2 ×2 and *5 alleles were observed. Conclusions: The steady state plasma concentrations of BX and 4OH were significantly low with CYP2D6 *10/*10 genotype, and their clinical implications need to be explored.(Supported by a grant NCC-0410590).

No significant financial relationships to disclose.
Randomized, multicenter, crossover phase II trial to compare exemestane (E) vs. anastrozole (A) in postmenopausal patients (pt) with advanced breast cancer (ABC) and positive hormone receptors (HR). Final efficacy analysis of GEICAM 2001–03 study
Authors: Mayordomo J. , Llombart A. , Martín M. , Antón A. , Barnadas A. , Antolín S. , Alés-Martínez J. , Álvarez I.
Published: March 2020

638

Background: Head-to-head comparison of a steroidal aromatase inhibitor (AI) (E) vs. a non-steroidal AI (A) with crossover at the time of progression to evaluate the sequence of administration. Principal and secondary objectives were overall response rate (ORR), clinical benefit (CB) and time to progression (TTP). Methods: Postmenopausal pt with measurable ABC and positive HR, were stratified [previous tamoxifen (tam) (yes vs. no), previous chemotherapy (ct) (yes vs. no) and stage (IIIb vs. IV)], and randomized to E (25mg/day), or A (1mg/day) until progression. As per Simon’s test, with a p1 of 25% ORR and a p0 of 10% ORR, α and β errors 0.05 and 10%, 50 pt per arm were needed. Results: 103 (51 vs. 52) pt were recruited between 2002 and 2004. Main pt characteristics: median age 70 and 73 years, 82 vs. 88% stage IV, 12 vs. 17% previous ct, 51 vs. 50% previous tam, median size of lesions of 5 vs. 4 cm, mean number of lesions of 1.4 in both arms. Most frequent site of lesions were breast (33 vs. 35%), lymph nodes (22% vs. 25%) and connective tissue (27% vs. 23%). Efficacy: For initial treatment ORR was 37% (CI95% 24–51) in arm E vs. 52% (CI95% 38–66) in arm A (p= 0.151). 47% of pt in E vs. 60% in A presented CB (p=0.202). Mean TTP for arm E was 8.1 months (m) (1.1–15.2) and for arm A was 12.1 m (6.6–17.6) (p=0.4716). 11 pt (arm E) and 12 (arm A) crossed-over after progression. Following crossover mean TTP for E was 4.4 m (3.7–5.1) and for second line A was 1.9 m (0.1–3.7) (p=0.0172). Conclusions: E and A seem to be equivalent in terms of efficacy as first treatment for postmenopausal pt with ABC and positive HR. We suggest a possible advantage of the steroidal AI, exemestane, following disease progression on the non-steroid AI anastrozole.

[Table: see text]
A multi-center study of the effects of toremifene (TOR) and anastrozole (ANA) on serum lipids and bone metabolism in postmenopausal patients with estrogen receptor (ER) positive breast cancer: Interim report
Authors: Mitsuyama S. , Yanagida Y. , Doihara H. , Komaki K. , Kusama M. , Ikeda T. , Kimura M. , Sano M. , Miyauchi K.
Published: March 2020

645

Background: We have already reported the data that the antiestrogen TOR has better effects than tamoxifen on serum lipid metabolism (ASCO 2003, Breast Cancer Res. Treat 2004). In this study, we evaluated the time course effects of TOR and ANA on serum lipids profile and bone metabolism in ER positive, postmenopausal breast cancer patients with adjuvant hormone therapy. This is the first study to compare TOR and ANA. Methods: Patients were randomly allocated to a TOR40mg/day group (36 cases) or an ANA1mg/day group (33 cases). Serum lipids were measured at before, and 6 and 12 months after the initiation of administration. Changes in the serum lipids and bone markers were compared. Results: Results of lipids: In the TOR group, total cholesterol (TC), LDL, ApoB and Triglyceride (TG) significantly decreased at 6 and/or 12 months compared with the values before the start of administration (p<0.05). HDL and ApoA1 significantly increased at 6 and 12 months in the TOR group (p<0.0002), but ApoA1 at 12 months also significantly increased in the ANA group (p=0.02). Between the TOR and ANA groups, the changes in the percentage of the values of TC, HDL, LDL, ApoA1 and ApoB were significantly different at 6 and/or 12 months (p<0.05). Results of bone markers: BAP significantly increased in the ANA group (p<0.0001); in contrast, NTx significantly decreased in the TOR group (p<0.0001). Between the TOR and ANA groups, the changes in the percentage of the values of BAP and NTx were significantly different at 6 and 12 months (p<0.005). Conclusions: TOR and ANA have different profiles. These findings indicate that TOR has beneficial effects on both lipids and bone metabolism in postmenopausal patients with breast cancer.

No significant financial relationships to disclose.
Pilot trial of a synthetic breakpoint peptide vaccine in patients with chronic myeloid leukemia (CML) and minimal disease
Authors: Maslak P. G. , Dao T. , Gupta S. , Gomez M. , Chanel S. , Korontsvit T. , Zakhaleva V. , Ashraf S. , Berman E. , Scheinberg D.
Published: March 2020

6514

Background: CML is characterized by a tumor-specific fusion oncoprotein, BCR-ABL. Peptides spanning the B3A2 breakpoint of BCR-ABL can elicit MHC restricted T cell responses and clinical responses. No such data have previously been reported for vaccines targeting B2A2. Methods: We initiated a clinical trial administering synthetic analog breakpoint specific peptide vaccines for either B3A2 or B2A2 breakpoints to CML patients with major or complete cytogenetic remission. Measurable minimal disease was determined by either quantitative polymerase chain reaction (RQ-PCR) or nested PCR for BCR-ABL. Vaccine was administered with GM-CSF and Montanide ISA 51 subcutaneously. Eleven vaccinations were planned over the course of 1 year with the first 5 doses administered bi-weekly. Results: Eleven of 20 planned patients have been accrued to the study. Eight had documented cytogenetic remission and 3 were BCR-ABL positive via FISH analysis. Seven of the 11 patients had measurable BCR-ABL transcript levels as determined by RQ-PCR and all 11 were positive using the nested technique. Of the 5 patients positive for BCR-ABL (by RQ-PCR) before vaccination, 3 converted from RQ-PCR positive to negative while the transcript levels in the other patients decreased by approximately 1 log after 5 doses. All 5 of these patients remained positive using the nested PCR technique. Vaccination was well tolerated with local skin reactions at the injection sites. Immunologic reactivity was assessed ex vivo by CD4 autologous proliferation assay and T cell interferon (IFN) secretion (ELISPOT) assay. Ten of 11 patients were immunologically unreactive to the peptides prior to the vaccinations. Following the 5th dose of vaccine, 8/8 patients (including 2 with B2A2) tested showed significant immunologic responses by one of the above assays. Conclusions: These preliminary results suggest vaccination with synthetic analog peptides derived from CML proteins results in immunologic responses and may be associated with molecular improvement. Clinical efficacy of these vaccines in reducing/ eliminating minimal disease has yet to be established.

[Table: see text]
Select high risk genetic features predict earlier progression following chemotherapy in chronic lymphocytic leukemia: Prospective randomized trial (Intergroup E2997) to evaluate justification for risk-adapted therapy
Authors: Grever M. R. , Dewald G. W. , Neuberg D. S. , Reed J. C. , Kitada S. , Flinn I. W. , Appelbaum F. R. , Larson R. A. , Tallman M. S. , Gribben J. G. , Byrd J. C.
Published: March 2020

6521

Background: Genomic features including lack of IgVH mutations, del(11q), del(17p), and p53 mutations have been reported to predict clinical course and overall survival in CLL patients (pts). Bcl-2 family proteins and ZAP-70 have also been explored as predictors in CLL. Methods: We prospectively evaluated the prognostic significance of clinical features and laboratory variables on response and progression-free survival (PFS) following treatment with fludarabine (F, n=132) or fludarabine plus cyclophosphamide (FC, n=137) as part of the US Intergroup Trial E2997 for previously untreated CLL. Results: FC therapy had higher complete response (CR) (23.4% versus 4.6%), overall response (OR) (74.3% versus 59%), and median PFS (31.6 mos versus 19.2 mos) compared to F. CR and OR were not significantly different based on interphase cytogenetics, IgVH status, or p53 mutation. IgVH status or levels of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 proteins were not associated with clinical response or PFS. IgVH status and ZAP-70 levels were associated with time from diagnosis to treatment. Using a model including treatment arm, pts with del(17p) or (11q) had significantly shorter PFS (hazard ratios 3.54 and 2.05 respectively). In pts with a p53 mutation without del(17p) there was no enhancement of the model predicting poorer outcome, nor did IgVH status enter the model for predicting PFS. Conclusions: Combination chemotherapy is associated with a higher CR, OR, and PFS. Also, initiation of therapy for pts with Rai stages 0/1 resulted in a higher response rate. Del(17p) and del(11q) are highly predictive of shortened PFS with fludarabine-based chemotherapy. IgVH and p53 mutational status, as well as expression of ZAP-70, Bcl-2 family proteins, and CD38, did not predict response or PFS. ZAP-70 expression is associated with cytogenetic subsets predicted to have a worse overall prognosis, but did not identify pts who will do poorly with therapy. A combination of clinical staging and cytogenetics provide support for future risk-stratified treatment of CLL. Pts with a projected short response duration can be identified for future investigational strategies.

No significant financial relationships to disclose.
Prognostic significance of WT-1 levels in patients with myelodysplastic syndrome and leukemia after reduced-intensity allogeneic transplantation
Authors: Michaelis L. C. , Sher D. , Myers M. , Siddiqui M. , Collins-Jones D. , Ulaszek J. , Huo D. , Wickrema A. , Van Besien K. , Stock W.
Published: March 2020

6524

Background: Expression of WT-1, a zinc-finger transcription factor, is elevated at diagnosis in many kinds of leukemia. The prognostic significance of the WT-1 transcript level before and after stem cell transplant is controversial. We performed real-time quantitative PCR (RQ-PCR) on samples from pts with leukemia and MDS undergoing allo stem-cell transplant (SCT) to determine if WT-1 expression correlates with survival (OS) and/or disease-free survival (DFS). Methods: Pts were conditioned with fludarabine, melphalan and alemtuzumab. cDNA was synthesized for RQ-PCR, which was performed on bone marrow (BM) and peripheral blood (PB) samples drawn prior to transplant admission and at day 28 (D28) post transplantation. All samples were analyzed using LightCycler technology and reported as a normalized ratio of WT-1 copy number to ABL copy number. Results: Data on 48 patients who underwent allo SCT are reported here. During a median follow up of 17 months, 24 patients died and the OS rate at one year was 52%. The DFS rate at one year was 34%. There was a statistically significant association between pretransplant WT-1 levels measured in PB and OS, with increase in risk of death by 36% for every 10 fold increase in WT-1 levels (p=0.048). Pretransplant WT-1 levels in both PB and BM also predicted DFS: the risk of relapse or death was increased by 44% (PB) and 71% (BM) for every 10 fold increase in WT-1 levels (p=0.012; p=0.048). However, after controlling for disease status at transplantation using a Cox model, pretransplant WT-1 levels were no longer a significant predictor because these levels were highly correlated with disease status at transplantation. We did not find any significant correlation between WT-1 levels 28 days post-transplantation and outcome. Conclusions: Our preliminary results differ from several published studies demonstrating prognostic significance of WT-1 RQ-PCR after allo SCT. Although elevated WT-1 levels prior to transplantation correlate with higher risk of post-transplant relapse and death from any cause, these preliminary data fail to establish an independent prognostic role for WT-1 RQ-PCR in the setting of reduced intensity allo SCT. Analysis of additional post-transplant time points is proceeding.

No significant financial relationships to disclose.