bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality indicators for end-of-life breast cancer care: Testing the use of administrative databases
Authors: Lethbridge L. , Grunfeld E. , Dewar R. , Johnston G. , McIntyre P. , Lawson B. , Burge F. , Dent S. , Paszat L. , Earle C.
Published: March 2020

6066

Background: Defining, measuring and monitoring quality of care is a facet of health services research that is growing in importance. Breast cancer offers a disease model to examine quality end-of-life (EOL) care provided to women. Administrative data have the unique potential to provide population-based measures of quality of care. The objective of this study was to assess the feasibility of using routinely-collected administrative data to measure quality EOL care for breast cancer patients. Methods: A cohort of all women in Nova Scotia who died of breast cancer between 01/01/1998 and 31/12/2002 was assembled from the Cancer Registry and Vital Statistics data. The EOL study period was defined as the last 6 months of life. A total of 864 women met the eligibility criteria. After a literature review, an expert panel identified 19 indicators that were potentially measurable through administrative data. Physician billings, hospital discharge abstracts and seniors pharmacare data, supplemented by clinical datasets, were utilized to calculate the statistics with which to represent the indicators. Results: Benchmark measures of care across the cohort show 63.4% died in a hospital, a mean continuity of care index of 0.786, and the mean number of inpatient days in the last 30 was 9.9. Indicators of aggressive care include 9.3% had chemotherapy in the last 14 days, 5.6% had more than 1 emergency room visit in the last 30 days, and 29.1% had more than 14 inpatient days in the last 30 days. Conclusions: Weaknesses of using these data include: 1) fixed variables with an administrative rather than a clinical objective; 2) lack of comprehensiveness of various datasets; and 3) the use of billings data where increasingly physicians are paid through methods other than fee-for-service. Strengths of this approach are: 1) population-based cohort; 2) comprehensiveness of cohort selection through the provincial Vital Statistics file; and 3) accessibility of data.

No significant financial relationships to disclose.
Potentially modifiable influences on cancer family history-taking among primary care physicians in Vermont and Massachusetts
Authors: Flynn B. S. , Wood M. E. , Dana G. S. , Ashikaga T.
Published: March 2020

6067

Background. Taking a complete family history is key in identifying individuals at increased risk for cancer. The objectives of this study were to test hypothesized relationships between potentially modifiable factors and family history-taking by primary care physicians. Methods. Primary care physicians (family medicine, internal medicine, gynecology) were surveyed by mail in Vermont, urban and suburban Boston (n=880) using comprehensive rosters from employers or state-wide networks, with a response rate of 70%. Measures of family history-taking quality and factors that may influence this behavior were developed systematically and validated using factor analysis methods. The primary outcome variable was either extent of history-taking or age of cancer diagnoses. These dependent variables were regressed on scales measuring physician perceptions of the advantages and disadvantages of history-taking, confidence in taking cancer family histories, supportive resources, and knowledge of management for patients at high risk for breast and colon cancer; relevant factors controlled in these multiple regressions included type and location of practice. Results. Most physician perception factors hypothesized to influence quality of history taking were found to be significantly associated in the analysis. The strongest predictor of extent of family history-taking was perceived disadvantages of taking a cancer family history (p<.001). Reports of supportive resources ((p<.01); perceived advantages (p=.02); and confidence (p=.02) were also associated with this behavior. Gathering age of cancer diagnoses was significantly associated with perceived advantages, supportive resources and confidence (all p<.0001). Knowledge of high risk management was not associated with quality of family history-taking in either analysis. Conclusions. Potentially modifiable resource and perception factors were significantly associated with quality of family history in a large and diverse sample of primary care physicians. Improving family history quality for identification of high risk individuals among primary care providers will need to address multiple factors.

No significant financial relationships to disclose.
Comparison of adjuvant chemotherapy use in African American women with breast cancer versus the rest of the adjuvant breast cancer population
Authors: Quigley J. M. , Bule W. , Runyun J. , Moseley A.
Published: March 2020

6069

Background: Demographics, specifically race have been discussed as reasons for disparity of care in the breast cancer setting. Methods: We used a validated database with physician entered, de-identified patient data from a randomized sample of oncologists in the US. Physicians capture de-identified data on up to 20 patients per week using a clinically validated, software driven algorithm. We evaluated all female patient records with breast cancer that were receiving adjuvant chemotherapy for their disease, from January 2005 through November 2005. All data elements are required fields, allowing for a complete patient record with each entry, including race, age, stage, nodal status, hormone status, her 2 status and chemotherapy treatments. Results: During this 11 month period, 4465 adjuvant breast cancer records were received. All were included in this analysis. Of the 4465 patient records, 69%( n=3085) were Caucasian, 18% (n= 830) were African American, 9% (n=408) were Hispanic/Latino and 4% were ‘other, which included, Native American and Asian patients. The average age for Caucasian patients was 56 years; average age for African American patients was 55 years, average age for Hispanic/Latino patients 51 years, average for all other patients 55 years. 63% of the Caucasian patients had node + disease, 59% of African Americans had node + disease, 62% of Hispanic/Latinos had node + disease, and 61% of all others had node + disease. Top treatment regimens for Caucasian patients were AC followed by Taxol (dose dense), AC, AC followed by Taxotere (dose dense), ACT (Taxotere) and CMF. Top treatment regimens for African Americans were AC followed by Taxol (dose dense), AC, AC followed by Taxotere (dose dense), ACT (Taxotere) and FAC. Conclusions: In this clinically similar patient population there was no difference in adjuvant chemotherapy selected based upon race. Further evaluations of treatment selections, including, surgery, radiation and endocrine therapy by race are warranted.

No significant financial relationships to disclose.
Salvage surgery for local recurrence after breast conservation therapy—Is re-lumpectomy an appropriate treatment?
Authors: Ofuchi T. , Amemiya A. , Ono M. , Hatayama J. , Takeda A.
Published: March 2020

608

Background: Since 1983 through 2005, 2439 clinical stage I or II patients (pts) were treated with lumpectomy and postoperative irradiation. During median follow-up of 75 months, 142 patients experienced local recurrence as first and sole event were judged as candidate for further local therapy. The purpose of this study is to evaluate the outcome of salvage treatment, with specific reference to feasibility of second breast conservation surgery. Methods: Among those with operable local recurrences, 73 pts who requested conservation of their breasts and whose recurrences were judged to be small enough to be locally re-excised with adequate margins underwent second lumpectomy (Re-LMP). 51 pts were treated by mastectomy with or without immediate reconstruction (MAS). Adjuvant systemic therapy of limited duration was given at the discretion of patients and therapists. Survival and local re-recurrence after salvage surgery were estimated by Kaplan-Meier method. Results: Age of patients ranged from 28–69 (mean: 41). Median follow-up length after salvage surgery was 53 months (6–194 months). Patient/Tumor characteristics were similar in Re-LMP and MAS groups. Local re-recurrence: Re-LMP: 31 pts developed in-breast re-recurrence (34% at 3yrs, 49% at 5yrs). MAS: 6 pts experienced chest wall recurrence (11% at 3yrs, 11% at 5yrs, p=0.0005). Independent risk factor for re-recurrence was not identified. Survival: In initial clinical stage I patients, 3 pts treated with Re-LMP died after salvage surgery and all treated with MAS survived (94% and 100% at 5yrs, p=0.2). In clinical stage II patients, 6 in Re-LMP and 8 patients in MAS died (89%, 57% at 5yrs after salvage surgery, p=0.02). Poor prognostic factors for both groups were initial stage and stage at the time of local failure. Conclusions: For an isolated in-breast recurrence, salvage mastectomy with or without immediate reconstruction provides excellent local control. At the present time, mastectomy should be offered as 1st treatment option. Although survival is not jeopardized, Re-LMP alone does not offer adequate local control. Additional local therapy i.e. re-radiotherapy or aggressive systemic therapy may improve this poor result. Prospective studies should be initiated.

No significant financial relationships to disclose.
Estimating the real cost of adjuvant (A) trastuxumab (T) in patients(pts) with HER-2+ (H+) early stage breast cancer (ESBC)
Authors: Wilson E. , Crown J. , Ballot J. , McDonnell D. , Sheehan E. , Healy J.
Published: March 2020

6081

Background: Pts with H+ metastatic (M) ESBC have a high risk of relapse. T has been reported to reduce the risk of relapse for pts with H+ESBC by approximately 50% when combined with A chemotherapy (CT). We attempted to study the real cost of AT in the context of current use of T in MBC (MT), and of the predicted reduction in the risk of relapse. Methods: We conducted a retrospective analysis of the mean per pt cost of AT and MT, and standard ACT in St. Vincent’s Hospital. The costs/pt for AT and MT were €34k, and €47k respectively, and for the listed agents in standard A: docetaxel(D)-8.8k, paclitaxel(P)-7.4 k, filgrastim(G)-9.3 k. Based on published/presented data (BCIRG 001), we assumed a 35% risk for relapse at five years for pts with H+BC receiving conventional A, and a 50% risk reduction (RR) for AT, giving an absolute benefit of 17.5%. We then devised an equation to calculate the Crp for AT: Crp=[a-M(NRA/104)]/[NRA/104] where a = cost per pt for treatment (Tx) with AT, M = cost per pt for Tx with T in MBC, N = % of pts relapsing after standard A, RA = % reduction in the risk of relapse after Tx with AT (over standard A). Results: The corresponding real T costs/100 pts for the following reductions in relapse rate would be:25%-€3.4m 50%-€2.6m-, 80%-€2.1m, 100%-€1.8m. The Crp for AT with a 50% reduction in relapse rate is €147k. With a 100% reduction in the RR we estimate the Crp to be €50k. We studied D (D-BCIRG 001), P (P-CALGB 9344) and G (G-CALGB 9741 dose-dense), and noted the following published absolute relapse reductions for these tx: D-7%, P-5% and G-4%. The following costs per relapse prevented were calculated: P-148 k; G-231k; D-126k. Conclusions: Using the equation, the real cost per relapse prevented of AT can be calculated, and comparisons made with the cost-effectiveness of other accepted A. Assuming no re-treatment with MT, AT appears to be a relatively cost-efficient means of reducing relapses. Reports of the efficacy of short AT regimens suggest the possibility of even greater cost-effectiveness. This equation could possibly be used to calculate the cost effectiveness of other novel A molecular therapies.

[Table: see text]
The use of warfarin for venous thromboembolism (VTE): Practical problems for patients and resource implications for an oncology unit
Authors: Morris P. G. , O’Dwyer D. , Davenport C. , O’Callaghan C. , Breathnach O. S. , Grogan L.
Published: March 2020

6088

Background: Recent evidence has suggested improved efficacy with low molecular weight heparin (LMWH) over oral coumarins for the treatment of cancer patients with VTE. Oral anticoagulants present multiple practical problems for patients undergoing chemotherapy, including side-effects, disruption of anticoagulation for invasive procedures, multiple drug interactions and multiplicity of patient visits. To assess the practice implications of these issues, a review was carried out in a busy medical oncology unit. Methods: A retrospective review of all patients treated with the coumarin derivative, warfarin for VTE during the last year was undertaken. Patients on prophylactic warfarin for central venous devices were excluded. Computerised laboratory records were used to identify patients. Patients were assessed for adverse events and therapeutic efficacy. The extra volume of work involved in monitoring blood tests and treating complications was quantified. Results: 55 patients with VTE were treated with warfarin from 07/01/04 to 06/30/05. The majority (73%) had metastatic carcinoma. 21 invasive interventions required disruption of anticoagulation. 90% of these were in patients with metastatic disease. Each patient was subtherapeutic (International normalised ratio <2.0) for a mean of 30.7 days (25% of mean duration of anticoagulation). There were 8 admissions for haemorrhage. Nine patients died on warfarin, 8 of whom had metastatic disease. In one patient with significant cardiac comorbidity warfarin therapy contributed to early death. No patterns of drug interactions were identified. A total of 1,369 coagulation tests were performed. There were 382 extra blood test visits, representing 26% of all day ward blood visits. On treatment, 13 patients (24%) were changed from warfarin therapy to LMWH. In 4 patients there was progression of VTE. In 9 patients, all with metastatic disease LMWH was substituted to qualitatively improve patient care by minimising hospital visits and facilitating home based care. Conclusions: This study identifies the high rate of treatment change to LMWH and quantifies the extra resource utilization with coumarin therapy. This supports the increased primary use of LMWH in selected cancer patients.

No significant financial relationships to disclose.
Influence of tumor type, disease status, and patient age on self-reported interest regarding participation in cancer clinical trials
Authors: Rivkin S. E. , Markman M. , Petersen J. , Montgomery R.
Published: March 2020

6100

Background: There is limited data available regarding the reasons cancer patients decide to enter clinical trials. Methods: To explore this issue, aggregate responses to the question, “Are you interested in learning about clinical trials for your condition?” obtained from > 115,000 cancer patients (or their families) who entered data into one of several proprietary decision-support programs embedded within approximately 100 cancer-related Internet sites, were analyzed. Results: The proportion of patients (or their families) who expressed interest in learning of the availability of clinical trials ranged from as low as 21% (endometrial and cervix cancer patients > 80 years old; n=178) to as high as 85% (recurrent ovarian cancer patients, aged 51–60; n=842). Patients > 80 years old, regardless of sex, tumor type, or disease status, were substantially less likely to desire such information. Patients with self-declared more “serious conditions” (e.g., metastatic breast cancer [71%; n=5,444], recurrent prostate cancer [70%; n=4,121]), and those with cancers widely known to have a poor prognosis (e.g., non-small cell lung cancer [75%; n=23,298]), were more likely to request data on trials, than those with an overall more “favorable” prognosis (e.g., newly diagnosed prostate cancer [46%; n=21,348]). There were no observed differences in interest between men and women with similar conditions. Conclusion: In this large data base, major differences in self-expressed interest regarding availability of clinical trails were observed. Particularly notable were the reduced interest among the very elderly, and the increased interest by patients with the most serious cancer-related conditions.

[Table: see text]
Assessment of nutrition in cancer patients and its effect on treatment outcome—A study from a developing country
Authors: Mukhopadhyay S. , Paul C. , Thander K. , Gorai J. , Purakayet M. , Biswas S. , Choudhury R. , Ahmed R. , Gupta P. , Mukhopadhyay A.
Published: March 2020

6125

Background: In developing countries one-third of the people suffer from mal-nutrition. It has been shown that a good nutritional status can reduce complications of treatment, strengthen the immune system and contribute to the patient’s general well being throughout treatment. A good nutritional status is therefore essential for optimal treatment of a cancer patient. The aim of our study was to see the nutritional status of cancer patients on diagnosis and effect of nutrition on outcome of therapy. Methods: In this study we prospectively analyzed the nutritional status of 500 cancer patients in Netaji Subhash Chandra Bose Cancer Research Institute, a tertiary cancer center of eastern India during period from January 2004 to December 2005. The age range of the patients was 19 years to 74 years (median age 46 years). The parameter analyzed were weight for age, total protein, serum albumin and mid arm circumference. The weight for age and mid arm circumference were taken as normal if they were between 3rd and 97th percentile curve of the growth chart recommended by the Indian Council of Medical Research. The albumin level and the total protein were considered normal if the value is equal to or more than 3gm% and 5.8gm%. Result: It was seen that total 120 patients (24%) were low weight for age and 100 patients (20%) had low mid arm circumference. Total 90 patients (18%) had low serum albumin while 130 patients (26%) were low serum protein. Low weight for age, low serum albumin and low mid arm circumference were significant factors in disease free survival and toxicity of chemotherapy (p value < .001) Conclusion: We conclude that mal-nutrition is a major finding in cancer patients in developing country like ours. The patient with mal-nutrition had less disease free survival and more toxicities during therapy as compared to well-nourished patients.

No significant financial relationships to disclose.
Laparoscopic treatment of endometrial cancer: A cost-effectiveness analysis
Authors: Abaid L. N. , Boggess J. , Wu J.
Published: March 2020

6127

Background: Endometrial cancer has traditionally been staged using an open abdominal incision. Laparoscopic staging offers the benefits of a minimally invasive approach and may also be economically advantageous. Methods: A decision model was developed to determine the cost-effectiveness of laparoscopy versus laparotomy for surgical staging of a hypothetical cohort of women, aged 35 to 80 years, with early-stage endometrial cancer. The analysis was performed from a societal perspective with a time horizon of six weeks. The primary outcome was cost-effectiveness, measured as cost per complete staging procedure. Parameters in the decision model included rates of mortality, intraoperative complications (bowel, bladder, or vascular injury and intraoperative hemorrhage), deep venous thrombosis (DVT), blood transfusion, and length of hospitalization. Assumptions included that laparoscopy and laparotomy were equally effective for staging, and that the length of hospitalization was one day for laparoscopy versus three days for laparotomy. Probability estimates were obtained from a review of the medical literature and from institutional data. Results: The cost for laparoscopic staging per subject was $14,616 compared to $16,184 for laparotomy. Thus, the incremental cost-effectiveness ratio (ICER) was $1,568 per complete staging procedure, and laparoscopy was more cost-effective than laparotomy. Based on one-way sensitivity analyses, the factor that had the greatest influence on the model was length of hospital stay after laparotomy. The ICER was insensitive to changes in the rates of mortality, intraoperative complications, and blood transfusions. Conclusions: Laparoscopic surgery for endometrial cancer is a cost-effective alternative to laparotomy, primarily because it reduces the length of the postoperative hospitalization.

No significant financial relationships to disclose.
Barriers and stimuli for genetic counseling among unaffected women at high risk for breast cancer
Authors: Cummings S. , Pakilit A. , Stolley M. , Khan S.
Published: March 2020

6144

Background: Genetic counseling (GC) is available to provide risk assessment and education about hereditary cancer, explore the medical and psychosocial impact of these risks, and to facilitate genetic testing (GT) and its complex interpretation. While the motivations for undergoing GT have been well documented, little is known about patient motives to initially seek GC. Current uptake of GC services does not match the number of eligible patients. This study attempted to characterize the barriers and stimuli for cancer GC among unaffected women at high risk for breast cancer. Methods: IRB approval was obtained for this qualitative interview study. 54 unaffected patients who received a cancer genetics referral from a high-risk breast clinic were invited to participate. 18 subjects completed written questionnaires and 60-min telephone interviews, which were audiotaped and transcribed. A detailed coding system was developed and N*Vivo software was used in order to identify themes in the factors affecting intent to pursue GC. Results: We identified four themes in the factors affecting uptake of GC: 1)patient understanding of GC, 2)patient awareness of increased cancer risk, 3) family-tied life events (e.g. reproduction, caretaking, death), and 4) support for GC from physicians and family. The most common theme was patient understanding of GC. Subjects did not seem to differentiate between GC and GT, and they deferred GC until they were prepared to undergo GT. Conclusion: We identified barriers and stimuli for GC that were similar to those previously described for GT. The misconception that GC automatically leads to GT, and the subsequent low uptake of GC referrals, may be influenced by the current practice of non-directive referrals. Providing more directive referrals for GC, without being directive about GT, may reduce barriers to GC.

No significant financial relationships to disclose.
Circulating tumor cells: Tools for monitoring and targets for therapy
Authors: Pachmann K. , Camara O. , Lobodasch K. , Dengler R. , Runnebaum I. , Hoeffken K. , Pachmann U.
Published: March 2020

617

Background: Analysis of peripheral blood may help to early monitor the process of dissemination of metastatic cells into vital organs . The true number of circulating epithelial tumor cells (CETC) being still controversial, we, omitting all possibly selective enrichment procedures, detect a considerable number of such cells in breast cancer patients. CETC have been shown to respond to therapy in exactly the same way as the primary tumor and we have now probed CETC for monitoring effectiveness of adjuvant therapy. Methods: CETC were monitored in 97 patients before and after each cycle during adjuvant therapy using fluorchrome labeled antibody against epithelial antigen and laser scanning fluorimetry. Results: CETC could be detected in all patients after surgery. Four different forms of therapy response were observed: Patients with 1) CETC from ER+PR+ tumors responding only marginally with appreciable numbers remaining after therapy. These patients (about 40% of patients) have remained in CR; 2) rapidly decreasing CETC,sometimes to below the threshold of detection. These patients, too, remained in CR; 3) constantly or intermittently increasing resistant cells. All these patients have experienced early relapse 5–24 months after diagnosis); 4) Most interestingly, some cells initially respond very well to therapy but show a renewed increase during continuing therapy. These patients, too, have relapsed. Conclusion: Prognostic factors deduced from the primary tumor cannot predict outcome for the individual patient, whereas our approach monitoring CETC allows real-time survey of therapy response in individual patients. We confirm the observation of low responsiveness of ER+ tumors also in disseminated cells, with dormant CETC in most cases, not eliminated by current therapies but also not leading to early relapse. In contrast, most patients with CETC increasing during therapy suffer early relapse. This indicates not only that these cells are an important indicator of imminent relapse but also distant metastases may be the result of growth or regrowth of these cells. In some patients treatment influences subpopulations differently with a resistant population emerging responsible for relapse.

No significant financial relationships to disclose.
Concurrent administration of weekly trastuzumab and adjuvant breast radiotherapy increases skin, esophageal, and cardiac acute toxicities
Authors: Belkacemi Y. , Gligorov J. , Laharie-Mineur H. , Marsiglia H. , Ozsahin M. , Azria D.
Published: March 2020

630

Background: Trastuzumab (T) combined with chemotherapy (CT) has been recently shown to improve the outcome in patients with HER2-positive breast cancer. Its administration either weekly or every 3 weeks for one year is recommended as adjuvant therapy. Nevertheless, little is known about the toxicity of radiotherapy (RT) and T administered concurrently. Methods: Since June 2005, 95 patients (pts) with stage II-III HER2-positive breast cancer were treated concurrently with adjuvant T and RT. At this time, 53 have completed their combined therapy. Median age was 48y and 22 pts were menopausal. Twelve and 41 pts received T weekly or every 3 weeks, respectively. Neoadjuvant CT using anthracyclin/taxane regimen was administered in 27 pts. T was initiated after the last cycle of anthracyclin. Hormonal treatment was given to 17 hormone-receptor positive pts. RT was delivered to the whole breast (45–50 Gy ± a 10 to 16 Gy-boost, n=24) or to the chest wall (50 Gy, n=29). Internal mammary chain (IMC) and supraclavicular nodes were irradiated in 41 pts. Toxicity assessment (dermatitis, esophagitis and left ventricular dysfunction) was implemented according to the CTC v3.0 criteria. Results: Grade (G) 2 or more skin and esophageal toxicities were observed in 27/53 (51%) and 7/53 (13%) pts, respectively. Post-RT left ventricular dysfunction was observed in 22 pts (G1 in 14, G2 in 6, and G3 in 2). In univariate analyses, unfavorable factors influencing G2 or more cardiac toxicity were postmenopausal status (p=0.03), IMC irradiation (p=0.005) and weekly T administration (p=0.0001). Multivariate analysis revealed the concurrent administration of weekly T and RT (WTRT) as an unfavorable independent prognostic factor for cardiac toxicity (p=0.0001) and for G2 or more dermatitis (p=0.05). The two unfavorable prognostic factors for esophagitis (G2 or more) were concurrent administration of WTRT (p=0.008) and total mastectomy (p=0.004). Conclusion: Our preliminary results show that in addition to increased skin and esophageal acute toxicities, concurrent administration of weekly T and RT significantly decreases the left ventricular ejection fraction compared to the 3-week schedule. Results for the whole cohort will be presented at the meeting.

No significant financial relationships to disclose.
Evaluation of a recombinant HER2 vaccine: Induction of specific antibodies, T-cells and preliminary activity in metastatic breast cancer patients
Authors: Limentani S. A. , Campone M. , Dorval T. , Tan-Chiu E. , Curigliano G. , De Boer R. , Canon J. , Bachelot T. , Louahed J. , Brichard V. G.
Published: March 2020

631

Background: We designed a vaccine to induce T cells able to recognize epitopes from HER2 and to engender a polyclonal antibody reponse. Methods: The vaccine is a recombinant HER2 protein, including its extra and part of its intra-cellular domains (ECD/ICD), combined with a potent immunologic adjuvant. Cohorts of patients with Stage II/III breast cancer (BC) received 20, 100 or 500 μg in the adjuvant setting. Treatment comprised of six vaccinations over 14 weeks, for the 500-μg dose, recall injections were given on weeks 34 and 38. The trial was extended to include an alternative vaccination schedule: 500 μg on days 0, 28 and 98. In an on-going trial, patients with metastatic BC treated in the first line setting are receiving the 500-μg treatment and being assessed for clinical response. Results: The vaccine was well tolerated, with no symptomatic cardiotoxicity. Antibody (Ab) response against ECD was dose-dependent, with 2/12, 9/14 and 14/15 immune responders in the respective cohorts after four vaccinations. Response was dose-related. Ab isotypes were analyzed in the 500 μg cohort: in 50% of patients, high levels of IgM (30–60%) against ECD were found after four vaccinations. The switch towards IgG was complete in all patients after six vaccinations. The efficacy of booster vaccinations was observed mainly in patients with low IgM after eight weeks. After two vaccinations, Ab titers on the alternative 500 μg vaccination schedule were as high as after four vaccinations utilizing the initial schedule. The anti-ECD antibodies in 11/15 patients (500 μg level) bound HER2-overexpressing breast-cancer cell lines. In sera from 2 patients tested thus far, the gene-expression resembled that of trastuzumab. Assays show that specific T cells were obtained; detailed analysis is continuing. Among metastatic patients, two showed evidence of tumor regression after vaccination. Conclusions: The HER2 vaccine was well tolerated and induced (dose-dependently) anti-ECD Ab that bound the HER2 receptor. Data suggest that the vaccine also induced specific T-cell immunity. The alternative vaccination schedule may increase the Ab titers. This data justifies further evaluation of this vaccine in the phase II/III setting.

[Table: see text]
Clinical significance of extranuclear expression of hormone receptors in breast cancer
Authors: Kim R. , Kaneko M. , Arihiro K. , Emi M. , Tanabe K. , Murakami S. , Osaki A. , Inai K.
Published: March 2020

644

Background: Hormone receptor (HR)-positive breast cancer cells grow through estrogen receptor (ER)-signaling pathways that mediate both genomic and nongenomic actions, which cross-talk with growth factors associated with resistance to tamoxifen. The aim of this study is to explore the clinical significance of extranuclear expression of ER and PR in the cross-talk between HR and growth factor signaling pathways. Methods: We examined the extranuclear expression of ER and PR in 219 primary breast cancers by immunohistochemical staining. Specimens showing such expression were further examined for the expression of pAkt and aromatase. Due to heterogeneity, staining was scored on the basis of intensity and distribution in the tumors. Results: Extranuclear expression of ER or PR was observed in 21 cases (9.5%), which included 4 cases (19.0%) for ER and 20 cases (95.2%) for PR. Among these patients, HER-2, pAkt, and aromatase-positivity were observed in 14 cases (66.6%), 13 cases (61.9%), and 14 cases (66.6%), respectively. On the basis of nuclear HR expression, 11 of these cases were categorized as ER-positive/PR-negative, while 2 were ER-negative/PR-positive. Of those 13 cases, increased pAkt staining was found in 11 cases (84.6%). In particular, among the 11 ER-positive/PR-negative, elevated pAkt and aromatase were found in 10 (90.9%; p<0.01) and 9 cases (81.8%), respectively. Conclusion: PR is more frequently expressed extranuclearly than ER in primary breast cancer, and extranuclear HRs cross-talk with the Akt/HER-2-signaling pathway and activation of aromatase, providing an explanation for the observation that aromatase inhibitors are more beneficial than tamoxifen for ER-positive/PR-negative patients.

No significant financial relationships to disclose.
The influence of PET/Gallium (P/G) status and high-dose rituximab (HDR) in patients (pts) with aggressive, large, B-cell lymphoma (LBCL) receiving autologous stem cell transplants (ASCT)
Authors: Alousi A. M. , Saliba R. M. , Okoroji G. , Hosing C. , Samuels B. I. , Champlin R. E. , Khouri I. F.
Published: March 2020

6518

Background: P/G status has been suggested to be an important predictor of outcome in pts with LBCL who receive an ASCT. Newer conditioning regimens which include HDR have been shown to improve results (Khouri, JCO, 2005). The influence of HDR on the outcome of pts based on P/G status has not been determined. Methods: A retrospective review of pts with chemo-sensitive, LBCL who received an ASCT on a research protocol at MD Anderson between 1995 and 2005 was performed. Results: A total of 188 pts were identified. Median age was 49 yrs with 108 (57%) male pts. 147 (78%) had de novo LBCL and 41 (22%) had an LBCL of follicular origin (LBCL-F). 83 (39%) pts received HDR with ASCT. At transplantation 95 pts (50%) were in PR, 71 pts (38%) in CRU and 22 pts (12%) in CR. 142 (76%) pts were P/G negative, 37 (20%) pts P/G positive and 9 (4%) pts unknown. The median follow-up was 44 months. Factors that were considered for outcome included: Age, IPI, # of prior chemotherapies, B2-microglobulin, disease status at transplant, HDR and P/G status. On multivariate analysis, P/G status and HDR were the only predictors for progression and PFS. Pts who were P/G negative and those that received HDR had a hazard ratio (HR) of 0.3 (p<0.001) and 0.5 (p=0.02) for progression, respectively. The cumulative incidence (CI) of progression and progression free survival (PFS) at 54 months according to HDR and P/G status are shown in the table below. P/G Status and HDR were also found to be predictive for pts with LBCL- F on univariate analysis, however due to the small numbers in this subset of pts, multivariate analysis could not be performed. Conclusions: These results suggest that pre-transplant P/G positive status increases the risk of progression of LBCL after ASCT. The addition of HDR to the transplant regimen decreases this risk irrespective of P/G status.

[Table: see text]

No significant financial relationships to disclose.
Dynamics of molecular response to dasatinib (BMS-354825) in patients (pts) with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib
Authors: Quintás-Cardama A. , Kantarjian H. , Jones D. , Talpaz M. , Jabbour E. , O’Brien S. , Luthra R. , Wierda W. , Nicaise C. , Cortes J.
Published: March 2020

6525

Background: Mutations in the BCR-ABL kinase domain are a common mechanism (40%) of imatinib-resistance. Dasatinib is 300-fold more potent than imatinib against Abl and has activity against all BCR-ABL mutants, except T315I. We investigated the molecular response to dasatinib in pts with CML intolerant or resistant to imatinib. Methods: Fifty-three pts in chronic (CP) (n=29), accelerated (AP) (n=14) and blast (BP) (n=10) phase CML received dasatinib for a median of 22 wks (range, 7 to 42). Pts had received a median of 4 therapies (range, 1 to 8) including imatinib (n=53), IFN (n=32), and AMN107 (n=9). Imatinib was stopped (41 resistant and 12 intolerant) after a median of 34 mo (range, 2.5 to 82). Quantitative reverse transcription PCR in peripheral blood samples was performed prior to dasatinib and every 3 mo thereafter. Median BCR-ABL/ABL ratio (%) at dasatinib start was 78.34 (range, 0.009 to 100). Twenty-four of 42 assessed pts harbored 16 different BCR-ABL mutants. The most common mutations were H396R (n=5), G250E (n=4), and M351T (n=3). Results: BCR-ABL reductions occurred in 48 (90%) pts: <1-log in 12 (23%) pts (7 CP, 2 AP, 3 BP) after a median of 12 wks (range, 4 to 38); >1-log in 15 (28%) pts (5 CP, 6 AP, 4 BP) after a median of 12 wks (range, 4 to 35); >2-logs in 10 (19%) pts (7 CP, 2 AP, 1 BP) after a median of 14.5 wks (range, 4 to 36) and >3-logs in 9 (17%) pts (5CP, 3 AP, 1 BP) after a median of 16 wks (range, 4 to 36). BCR-ABL/ABL ratio <0.05 was seen in 5 (9.5%) CP pts. After a median follow-up of 26 wks (range, 6 to 41), 12 (23%) pts stopped dasatinib due to death (n=2), disease progression (n=6), BMT (n=1), or intolerance (n=3). Dose reductions (31/53, 58%) were associated with BCR-ABL increments in 13 pts (>1 log in 10). Twenty-nine (55%) pts had at least 1 follow-up PCR analysis after their lowest transcript level, and in 9 pts the BCR-ABL/ABL ratio increased >1 log (F359V, Y253H, S348L, H396P, F317L, G250E, F359C), in 4 pts >2 logs (E255V/K, V299L) and in 2 pts >3 logs (F359V, H396R). T315 mutants have not been detected. Conclusion: Dasatinib is associated with significant molecular responses in imatinib-resistant/intolerant CML across multiple BCR-ABL mutants. Longer follow-up is needed to define the stability and durability of these responses.

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Intravenous (i.v.) busulfan (Bu) plus melphalan (Mel) is a well-tolerated preparative regimen for stem cell transplantation (SCT) in patients (pts) with advanced lymphoid malignancies
Authors: Kebriaei P. , Madden T. , Thapar N. , Shpall E. , Hosing C. , Qazilbash M. , Thall P. , Khouri I. , Champlin R. , Jones R. , Andersson B.
Published: March 2020

6548

Background: High dose chemotherapy and SCT is an accepted treatment option for pts with relapsed lymphoid malignancies. However, relapse remains a significant problem. A double alkylating regimen of Bu and Mel has been suggested as an effective and myeloablative pre-transplant conditioning regimen. Historically, oral Bu was used and the combination resulted in considerable mucositis and VOD. An i.v. formulation of Bu has been developed that has less pharmacokinetic variability. We are investigating i.v. Bu-Mel in pts with lymphoid malignancies undergoing auto- or allo-SCT. Patients and Methods: The conditioning regimen consists of i.v. Bu 130 mg/m2 over 3 hr daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 μMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. After the 4 daily Bu doses, there is a rest day, followed by 2 daily doses of Mel at 70mg/m2. Stem cells are infused the following day. Dilantin is given for seizure prophylaxis. GVHD prophylaxis is tacrolimus and methotrexate for pts receiving allo-SCT. Results: Patient characteristics, engraftment, and regimen-related toxicities are listed below: Grade I or II mucositis was the most common regimen-related toxicity. There were no cases of VOD; reversible hyperbilirubinemia was observed in 3 pts receiving allo-SCT. No grade IV toxicity was noted, and there were no regimen-related deaths with longest follow-up of 10 months. All allo-SCT pts had 100% donor chimerism by day 30. 27 pts had i.v. Bu delivered per test dose guidance; 6 pts received fixed dose Bu at 130 mg/m2. The median daily systemic Bu exposure was 4867 μMol-min. Conclusion: Intravenous Bu-Mel is well tolerated, and enables prompt neutrophil and platelet engraftment. Individualized PK-directed dosing of i.v. Bu is feasible, and likely contributes to the low toxicity profile of this regimen. Longer time is needed to assess disease control.

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No significant financial relationships to disclose.
Similarities and differences in aging and in malignant transformation of human hematopoietic stem cells
Authors: Lannert H. , Able T. , Franz T. , Hofmann R. , Lenze A. , Horsch K. , Eckstein V. , Saffrich R. , Ho A. D.
Published: March 2020

6555

Background: The tracking of stem cell aging, differentiation and deterioration by gene expression profiling and proteome analysis allows the comparison of different stages. The overall aim of a proteomic study is characterization of the complex network of cell regulation. We focused our investigations on different subsets of highly enriched CD34+ stem cells from different human origins: fetal liver, cord blood, bone marrow (BM), and mobilized stem cells from peripheral blood (PBSC), as well as CD34+ leukemia cells, thus e.g. to identify pathways and new targets for leukemia therapy. Methods: Mononuclear cells were isolated by a standard Ficoll separation method from the different blood sources. An Auto-MACS (Miltenyi) and FACS Vantage SE cell sorter (Becton Dickinson) was used to highly enrich (>99%) CD34+ cells fractions. Sample preparation: Total RNA was isolated from sorted 1 × 10e6 cells by standard methods using RNA isolation kit (Qiagen). For gene expression analysis topic-defined PIQOR stem cell microarrays (936 genes) were performed. Proteomics started with the determination of protein concentrations, 2D-gel-electrophoresis were described in Proteome Works System (BioRad). Sypro ruby and/or coomasie stained gels were used for protein identification by Q-TOF analyses. The subcellular localization of the identified proteins were performed by fluorescence and confocal microscopy of all cell fractions. Results: 1. The microarray gene expression correlation shows many similarities between human healthy stem cells of different sources and ages, otherwise many differences: 125 upregulated genes (kinases: PAK1, ATM1, CDKN2A) and 32 downregulated genes (EBCTF, RAMP1) in malignant cells compared to healthy stem cells. 2. Proteomics analyses of the different cell fractions show a large overlap of the most dominant protein spots, >200 spots were identified by Q-TOF. For example stathmin (oncoprotein Op18) is expressed at very high levels in leukemia cells and in PBSCs but not in BM cells, additionally demonstrated by fluorescence microscopy. Conclusions: Combining genomics and proteomics assays, pathways e.g. Op18 for proliferation and migration of healthy (mobilized) CD34+ cells from bone marrow and malignant leukemia cells could be identified.

No significant financial relationships to disclose.
Delaying therapy in Pts age ≥ 65 with untreated AML
Authors: Estey E. , Giles F. , Garcia-Manero G. , Kantarjian H.
Published: March 2020

6560

186 pts age ≥ 65 with untreated normal karyotype AML given ara-C-containing Rx at MDA from 1996–2005 had course 1(C1) CR and death rates of 57% and 13%, while in 133 pts with abnormalities of chromosomes 5 and/or 7 (−5/−7) the C1 CR rate was essentially identical to the C1 death rate (30% and 27%). Knowledge of cytogenetics, while thus valuable in planning Rx, may not be available for ≥ 1 week after presentation, raising questions as to the advisability of waiting this long to begin Rx. We previously reported a multivariate analysis in 197 pts, median age 64 and with presenting WBC < 50,000, given idarubicin + ara-C for untreated AML at M.D. Anderson between 2001- and 2004, finding that the independent predictors of CR were age and cytogenetics but not the number of days from MDA presentation to MDA Rx (Estey et al. 2004 ASH meeting,abstract #879). Because Rx was delayed for > 1 week in only small numbers of older pts we now extend these observations to 684 pts age ≥ 65 with untreated AML and presenting WBC < 50,000 given induction Rx (± ara-C) at MDA since 1996. Time from MDA presentation to Rx was < 1 week in 423, 1–2 weeks in 126, 2 weeks-1 month in 80, and > 1 month in 55. This time was not affected by age, bilirubin, creatinine, or by whether induction Rx contained ara-C. However, 7% of pts Rxed within 2 weeks of diagnosis had performance status 3–4 vs. only 1% of pts Rxed after a delay of > 14 days (p = 0.008), leading us to limit analysis to pts with performance status 0–2. Results were as follows: Although CR rates were higher, results were qualitatively similar considering only pts given ara-C-containing Rx. Recognizing the potential influence of unrecorded covariates, the data suggest that delay of Rx in pts age ≥ 64 with untreated AML, WBC count < 50,000, and performance status < 3 does not affect outcome of induction therapy, a possibility given more credence by the several days that elapse between diagnosis of AML by referring physicians and MDA presentation. Delaying Rx allows knowledge of cytogenetic status, thus permitting investigational Rx, or supportive care only, to be directed to pts with -5/-7.

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No significant financial relationships to disclose.
A phase I trial of bexarotene, a retinoid X receptor agonist, in relapsed or refractory non-M3 acute myeloid leukemia (AML)
Authors: Tsai D. E. , Luger S. M. , Loren A. W. , Kemner A. , Thompson J. , Schuster S. J. , Perl A. , Porter D. L. , Bagg A. , Carroll M.
Published: March 2020

6567

Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with relapsed or refractory non-M3 AML. Methods: Bexarotene was administered orally daily until disease progression occurred. Five dose levels ranging from 100 to 300 mg/m2 were planned. Dose escalation occurred in cohorts of 3–6 patients based on dose-limiting toxicity. Results: Fourteen patients have been enrolled in 4 dose cohorts (100–250 mg/m2) with enrollment demographics: 8M/6F, median age 63 (range 51–76), 6 prior MDS, 6 primary refractory, median number of induction attempts 2, prior autologous stem cell transplant 4, 14 blood transfusion dependent, 12 platelet transfusion dependent, and 12 neutropenic. Two patients developed hypothyroidism. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade 2 or 3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea/hypoxia, pleural/pericardial effusions, weight gain/edema and dry cough in the setting of a rapidly rising neutrophil count. This syndrome resolved within 48 hours of stopping bexarotene and initiating steroids. One patient had a WBC rise from 1.7×103/μL (ANC 1,037/μL, 18% blasts) pre-bexarotene to 23.9×103/μL (ANC 19,368/μL, 3% blasts) during this syndrome. Flow cell sorted peripheral blood neutrophils all contained this patient’s original t(8;21) by FISH, suggesting differentiation of the leukemic blasts. Bone marrow blasts decreased to ≤5% in two patients. Three platelet transfusion dependent patients had increases in their platelet counts to a peak count of 40–292×103/μL on bexarotene. Conclusion: Daily oral bexarotene is well tolerated at the dose levels studied to date. Early evidence for activity has been seen as exemplified by improvement in platelet counts, decreased bone marrow blast counts, blast differentiation and possible retinoic acid syndrome. Patient enrollment is ongoing.

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