bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of race/ethnicity and treatment delay on breast cancer survival
Authors: Sheinfeld Gorin S. , Heck J. E. , Cheng B. , Smith S.
Published: March 2020

6063

Background: Several papers have examined the relationship between treatment delay and survival among patients who are diagnosed with cancer. None has yet relied on a large, population-based dataset to systematically examine survival among women within different ethnic/racial groups who delay breast cancer treatment. Methods: Subjects were 49,865 female Medicare enrollees age 65 and older who were diagnosed with breast cancer between 1992 and 1999 and identified by the Surveillance, Epidemiology, and End Results (SEER) program. Dates of their health care visits were identified through the linkage of SEER with Medicare claims data. Mortality from breast cancer was assessed through linkage with death certificates. Propensity score analyses that compared patients matched according to their propensity to receive treatment were used to balance patient characteristics between treatment groups, as would occur in a randomized clinical trial. Results: A propensity score analysis and a Cox proportional hazards model of survival (with adjustments for ER/PR status, treatment type, race/ethnicity, stage, age, comorbidities, marital status, poverty status, geographic location, and average number of service contacts) revealed that subjects with 1-month delay in the start of treatment had a reduced likelihood of survival (adjusted HR=1.17, 95% CI, 1.06–1.30) relative to those with less delay. Blacks had significantly lessened survival than women in other races/ethnicities (adjusted HR=1.23, 95% CI, 1.00–1.52). Receipt of radiation (adjusted HR=1.45, 95% CI, 1.24–1.69), chemotherapy (adjusted HR=1.73, 95% CI, 1.51–1.99), stage three diagnosis (adjusted HR=1.35, 95% CI, 1.08–1.70), being age 70 or older (adjusted HR=1.24, 95% CI, 1.09–1.41), or having 2 or more comorbidities (adjusted HR=1.47, 95% CI, 1.12–1.92) also predicted reduced survival from breast cancer. Conclusions: One month delay in accessing breast cancer treatment has a clear relationship to reduced survival, particularly among older, later-stage, comorbid black women who receive chemotherapy or radiation. Mechanisms for rapid access to treatment, using both provider- and system-based strategies, are recommended for these women who are at increased risk for breast cancer-related mortality.

No significant financial relationships to disclose.
Routine use of sentinel lymph node surgery in patients undergoing prophylactic mastectomy: A decision analysis model
Authors: Boughey J. C. , Cormier J. N. , Xing Y. , Meric-Bernstam F. , Ross M. I. , Babiera G. V. , Ames F. C. , Hunt K. K. , Bedrosian I.
Published: March 2020

607

Background: Patients with invasive carcinoma identified following prophylactic mastectomy (PM) require axillary lymph node dissection (ALND) for nodal staging as standard surgical treatment. Since most patients will be node negative, sentinel lymph node (SLN) surgery has been advocated to avoid the sequelae of unnecessary axillary surgery. However, since SLN surgery is not without complications and the incidence of invasive cancer in PM is extremely low, we sought to compare surgical strategies using a decision analysis model in order to define the true risks and benefits of routine SLN surgery versus standard surgical treatment (ALND). Methods: Model estimates were derived by systematic review of the literature. The outcomes examined were: (1) the number of SLN procedures that would need to be performed to avoid one ALND in a pathologically node negative patient; and (2) the probability of long-term axillary complications with each strategy. Occult breast cancer was defined as invasive cancer in the PM specimen and/or SLN metastases. Results: The following weighted averages were used to inform the model: i) incidence of invasive cancer in PM of 1%, ii) incidence of nodal disease of 25% in the presence of invasive breast cancer and 1% in the absence of invasive cancer in the breast, and iii) incidence of complications after ALND of 30% and after SLN surgery of 6%. Routine use of SLN surgery doubled the sensitivity for detection of carcinoma compared to ALND. However, 133 SLN procedures were required to avoid one ALND in a node negative PM patient. Additionally, the probability of complications per breast cancer detected was 10-fold greater with the SLN strategy. When the risk of breast cancer was projected at 10%, 13 SLN procedures were required to avoid one negative ALND and the complication rate per cancer detected was 2-fold greater in the SLN arm. Conclusions: The benefit of adding SLN surgery in patients undergoing PM depends on the probability of detecting invasive cancer. Routine SLN surgery in PM is not warranted given the large number of procedures required to benefit one patient and the complications associated with performing SLN surgery in all patients. However, the SLN strategy may be appropriate for subgroups of patients at higher risk of occult carcinoma.

No significant financial relationships to disclose.
Poor access to clinical trials among community cancer patients requiring chemotherapy for recurrent or progressive disease: Limitations of current cancer cooperative groups
Authors: Meyer L. A. , Lee J. A. , Mathiason M. A. , Frisby K. A. , Bruden K. C. , Meyer C. M. , Keller J. K. , Go R. S.
Published: March 2020

6076

Background: Data on clinical trial accrual among cancer patients treated in the community are limited. In a prospective study at our community-based cancer center, we found that the accrual rate was only 4% for newly diagnosed patients and protocol limitations accounted for 68% of non-accrual (Go RS, et al. Cancer 2006). We would like to determine the availability of trials for adult cancer patients with recurrent or progressive disease treated in the community and the accrual rate. Methods: We retrospectively identified this specific group of patients who received chemotherapy at our institution between November 2004 and October 2005 and collected data on the number, types, and sources of trials that were available. Results: We identified a total of 140 patients. There was an equal number of females (52.9%) and males, with a median age of 66 years (range, 38–89) at the time of chemotherapy. Fifty trials were available, with about half for the following cancers: lung (14%), pancreatic (12%), renal (10%), head and neck (8%), prostate (6%), and breast (6%). No trials were available for bladder, colorectal, and gastroesophageal cancers. The proportions of phase I, II, and III trials were 4%, 62%, and 34%, respectively. The sources of trials were: ECOG (56%), Wisconsin Oncology Network (14%), Intergroup (12%), GOG (10%), RTOG (2%), CTSU (2%), our institution (2%), and pharmaceutical companies (2%). Only 69 (49.3%) patients had trials appropriate for their type and stage of cancers. Among those patients with available trials, 24 (34.8%) were eligible to participate and 6 were enrolled, for an overall accrual rate of 4.3%. There were no differences in age and sex among subgroups in terms of trial availability, eligibility, and accrual. Conclusions: At our institution, enrollment of cancer patients with recurrent or progressive disease in clinical trials is as low as for newly diagnosed patients. Over 80% of the patients were denied access to a trial because of protocol unavailability and ineligibility. Current cancer cooperative groups do not provide adequate trials for patients in the community.

No significant financial relationships to disclose.
The potential for lost productivity in lung cancer patients
Authors: Zawisza D. , Pepe C. , Mittmann N. , Feld R. , Shepherd F. , Leighl N.
Published: March 2020

6093

Background: Lung cancer significantly impacts on a patient’s personal and professional life. Little is known about lung cancer patients’ lost productivity, which in turn has an important effect on society. We undertook this descriptive study to learn about lost productivity experienced by lung cancer patients and their caregivers. Methods: 40 consecutive patients attending outpatient lung clinics at a major cancer centre completed questionnaires assessing demographic details, patient and caregiver productivity, and quality of life (EQ5D, FACT-L). Results: 52.5% of respondents were male. Median age was 67 years (range 36 -81). Median disclosed income was $20,000–$39,999; 46.2% had pursued post-secondary training. 70% were ex-smokers, 40% had NSCLC, 27% SCLC, while a third did not know their diagnosis. Treatments received included IV chemotherapy (62.5%), oral therapy (20%), radiation (55%), surgery (42.5%) and 5% no treatment. Over 25% were working full-time prior to diagnosis, 40% were retired. None were able to continue full-time employment; 20% required disability or sick leave. 8 (20%) were able to work part-time. Of those still working, a median of 14 h were missed due to illness in the preceding 3 weeks, with a median of 32 h worked in that period. Patients reported an overall moderate (5/10) impact on their productivity and a significant (6/10) impact on their daily activities attributable to their cancer. Only 8.5% of patients received paid assistance, while 76% had their spouse, relative or friend as an unpaid caregiver. In the preceding 3 weeks, caregivers who assisted patients provided a median 24h of care; 25% of caregivers missed a median 12h of work. Overall, mobility, self-care and anxiety/depression were rated as mildly affected (1/3), while daily activities and pain/discomfort were rated as moderately affected (2/3). Median overall health state rated by the respondents was 60 {scale 0(worst)-100(best)}. Quality of life overall was poor - FACT-L median score was 93.2 (range 50 to 125). Conclusion: Lung cancer negatively impacts work productivity and significantly impairs activity. While many lung cancer patients are retired, there is a significant burden on caregivers, which may result in a substantial burden to society in lost productivity.

No significant financial relationships to disclose.
Aggressiveness of cancer-care near the end of life
Authors: Keam B. , Kim J. , Hong Y. , Lee S. , Kim D. , Im S. , Kim T. , Heo D. , Bang Y. , Kim N.
Published: March 2020

6103

Background: The objective of this study were to observe the markers of aggressive care in cancer patients including appropriateness of chemotherapy and to evaluate the trends in cancer-care and to assess their association with the availability of related health care resources. Methods: We designed restrospective cohort composed of patients who diagnosed as metastatic cancer and received palliative chemotherapy at Seoul National University Hospital in 2002. Hematologic malignancy and hepatocellular carcinoma with local treatment alone were excluded. Two hundreds ninety eight patients who died of cancer were finally evaluated the appropriateness of cancer-care including chemotherapy. Results: The median duration of chemotherapy was 6.02 months (mo) compared to 8.67 mo of median overall survival. Median periods between last chemotherapy and death were 2.02 mo. Among the 298 patients, 50.3% of the patients received chemotherapy in the last two months of life. Furthermore, 17 patients (5.7%) died within 2 weeks after receiving chemotherapy. It seemed that the patients had not enough time to prepare the death with dignity. The mean number of regimens and cycles the patients had received were 1.83 and 5.52, respectively. However, timing of discontinuance chemotherapy did not affect use of chemotherapy that there was no difference in numbers of regimens and cycles according to months between last chemotherapy and death. The proportion with >1 ER visit in the last months of life were 33.6% and average numbers of ER visits after cancer diagnosed were 1.72. Only 9.1% of patients referred to hospice center and 11.7% of patients agreed with written DNR. The lack of hospice centers and harmony with referring system in Korea might affect to this results. Conclusions: Among the patients who died of cancer, significant portion of patients received chemotherapy till the end of life as well as ER visiting. Relatively, hospice referral and discussions about DNR did not conducted well in end of life care. Not to interfere the dignity of life, the physicians should be concerned whether the patients dying of cancer are overtreated with chemotherapy and receiving the appropriate cancer-care.

No significant financial relationships to disclose.
Evaluation of comparative survival based on the AJCC 5th and 6th editions for breast cancer staging: 25 year experience in two southwest Washington state community cancer programs
Authors: Kim E. , Sanghvi P. , Marquez C. , Kim C. R. , Thomas C. R.
Published: March 2020

6118

Background: The revised American Joint Committee on Cancer (AJCC) sixth edition (6th ed.) cancer staging system increased stratification within breast cancer (BC) stages II and III defined by the AJCC 5th ed. system. The specific aim of this study was to determine and compare disease-free survival (DFS) for stage 0-III breast carcinoma between the 5th and 6th editions using retrospective data gathered from 1980–2004 in southwest Washington state (WA). Methods: 4,810 patients (pts) were identified using cancer registries at Saint John Medical Center in Longview, WA and Southwest Washington Medical Center in Vancouver, WA. Patients were restaged retrospectively using the 5th and 6th ed. systems. DFS was determined using the Kaplan-Meier method and compared using the log-rank test. Results: The age at diagnosis ranged 20–99 yrs, with a mean age = 60. The mean length for disease-free follow-up was 224 mos. Stage 0 and stage 1 criteria were unchanged between editions, and 10-yr DFS was 94% and 87% for stage 0 and stage 1, respectively. In stage II pts, 13% (199/1,519) were upstaged to stage III by the 6th ed. criteria, significantly improving the 10-yr DFS for stage II from 66% (5th ed.) to 72% (6th ed; p = 0.003). The majority, 85% (167/199), of pts upstaged were from the 539 classified as stage IIb disease by the 5th ed. This accompanied an increase in the 10-year DFS for stage IIb from 54% (fifth) to 62% (sixth; p = 0.046). The number of pts with stage III disease increased from 313 to 588 in the 6th ed. 10-year DFS increased from 30% to 36% (p = 0.025), respectively. Most of this increase resulted from changes within stage IIIa, as DFS increased from 32% to 41% (p = 0.046). When compared, DFS outcomes between stage IIIb and IIIc were not found to be statistically significant (p = 0.501). Conclusions: The AJCC 6th ed. system for BC provides greater distinctions between stages compared to the 5th ed., and reclassification results in significant changes in projected outcomes. However, the addition of the IIIc substage does not seem to show the same significant distinction when compared to the existing stage IIIb substage in outcomes.

No significant financial relationships to disclose.
A feasibility study of [11C]choline for the molecular imaging of human breast cancer in vivo using positron emission tomography (PET)
Authors: Kenny L. M. , Coombes R. C. , Al-Nahhas A. , Osman S. , Lowdell C. , Aboagye E.
Published: March 2020

613

Background: [11C]Choline is a novel PET radiotracer. Preclinical studies suggest that it may be promising in breast cancer. [11C]Choline has been recently evaluated as a screening agent in prostate cancer, but no studies have yet investigated its potential in breast cancer. We report a pilot study evaluating the utility and reproducibility of [11C]Choline-PET in breast cancer. Methods: Dynamic imaging was performed on an ECAT962 HR+ PET scanner for 65 min after intravenous injection with 190–369 MBq [11C]choline. Patients with locally advanced and metastatic breast cancer were eligible. All histological subtypes were included (ductal, lobular, and inflammatory). Arterial blood samples were taken continuously for 10 min, with 8 discrete samples up to 60 min to measure [11C]choline and metabolites. Tissue uptake was determined by standardised uptake value at 60 min (SUV, dose and BSA corrected) and Ki (irreversible trapping) calculated using Patlak (corrected for [11C]choline metabolites in plasma) and modified Patlak analysis (corrected for plasma + tissue metabolites). Reproduciblilty scans were performed 2–17 days later in the absence of treatment. Results: Tumour [11C]choline uptake was observed in 10 out of 11 patients (12 out of 13 distinct lesions). There was a significant difference between tumour and normal tissue (breast/lung) in [11C]choline uptake for Ki (p<0.0001) and SUV (p<0.0001). Tissue uptake was of the order lung ≤ normal breast < tumour < liver ≤ spleen. [11C]choline was rapidly metabolised, at 60 min the mean ± S.E. plasma radioactivity due to [11C]choline was 16.4 ± 2.9%. [11C]Choline uptake was found to be reproducible for Ki (modified Patlak: r=0.93, p<0.0001, Patlak: r=0.85, p=0.002) and SUV (r=0.94, p<0.0001) - measured in 8 patients (median of 2 days after the 1st scan). Tumour Patlak Ki was 13.2% > Ki calculated using modified Patlak analysis. Conclusions: [11C]Choline-PET imaging of breast cancer is promising and warrants further evaluation. Tumour [11C]Choline uptake measured by Ki and SUV is reproducible. We plan to study the relationship between choline uptake measured by PET and immunoassays of tumour samples. Functional imaging could have a vital role to determine the efficacy of target-specific agents.

No significant financial relationships to disclose.
Characteristics and outcomes of patients receiving chemotherapy in a cancer center ICU: A 5 year retrospective
Authors: Raoof N. D. , Knott M. , Pastores S. M. , Voigt L. P. , Halpern N. A.
Published: March 2020

6134

Background: Administration of chemotherapy is traditionally guided by functional status, and chemotherapy is commonly withheld from very sick people. In our ICU, we observed that we customarily administered chemotherapy to patients in multisystem organ failure. Very little has been published in the literature on this topic, therefore we sought to characterize patients who received chemotherapy during their intensive care unit (ICU) admission in a cancer hospital over a 5-year period. Methods: We evaluated all ICU admissions receiving chemotherapy between October 1998 and September 2003. If patients had multiple admissions, only the first was included. We analyzed age, gender, MPM-II scores, and ICU and hospital length of stay (LOS). Additionally, we identified patients who were on mechanical ventilation, vasopressors or were treated with renal replacement therapy at the initiation of chemotherapy. Mortality at ICU discharge, hospital discharge, and at 6 months and one year post hospital discharge were also determined. Results: During the study period, 4.2% (111/2,645) of all ICU admissions received chemotherapy, averaging 22.2 administrations per year. Only first admissions (a total of 103 patients; 60 men and 43 women) were analyzed. Average age was 51.4 years, with an MPM-II score of 53%, an ICU LOS of 9.1 days and a hospital LOS of 30.6 days. Although over a third of patients were on mechanical ventilation when chemotherapy was initiated, ICU mortality was only 23%. In contrast, all in hospital mortality was 46%. ( Table ) Conclusions: Most patients were critically ill when chemotherapy was administered but survived to ICU discharge. However, only 24% of patients were alive at one year. Whether chemotherapy should be considered a useful component of ICU care for cancer patients requires further study.

[Table: see text]

No significant financial relationships to disclose.
Multidisciplinary system for detecting medication errors in antineoplastic chemotherapy
Authors: Almenar-Cubells D. , Jimenez Torres V. , Serrano Fabia A. , Albert Mari A. , Molins Palau C. , Bosch Roig C. , Olmos Anton S. , Jimenez Arenas V. , Muñoz Langa J. , Llorente Domenech R.
Published: March 2020

6136

Background: The aim of this study is to quantify medication errors (ME) in a multidisciplinary system with a Computerized Pharmacotherapy Process (CPP) in cancer patients. Methods: Longitudinal, prospective, and cohorts study during 2 years (January, 2003-December, 2004) in adult patients who received antineoplastic treatment in Oncology and Haematology services. ME were identified by double cross-validation of every stage of the pharmacotherapy process (prescription, preparation, dispensation, administration and follow-up) carried out by the multidisciplinary team (physician, pharmacist, nurse) with CPP assistance. Variables: number of ME for 1000 patients-day, % according to the stage of the process and severity (scale to 1 -not damage in the patient- to 5 -irreversible damage-) of ME intercepted. Results: 638 patients were on treatment and ME were identified in 225 (35%). On a total of 18,785 preparations and 13,206 patients-day, 276 ME were detected, equivalent to 20.9 ME by 1000 patients-day (95%CI: 18.5–23.5); of these 16.8 ME for 1000 patients-day (80.1%) were intercepted and did not reach a patient (95%CI: 14.6–19.1). ME detected distribution according to the stage were: prescription 75.7% (95%CI: 70.2–80.7), preparation 21.0% (95%CI: 16.4–26.3), dispensation 1.8% (95%CI: 0.6–4.2), administration 1.1% (95%CI: 0.2–3.1), and follow-up 0.4% (95%CI: 0.01–2.0). ME distribution according to the severity were: grade 1: 15.9% (95%CI: 11.8–20.8), grade 2: 49.6% (95%CI: 43.6–55.7), grade 3: 33.7% (95%CI: 28.1–39.6), grade 4: 0.7% (95%CI: 0.1–1.6) and none of grade 5. The system intercepted 98.9% (95%CI: 94.3–99.9) of ME with severity equal or greater than 3 -ME with potential to damage the patient- and 70.2% (95%CI: 62.9–76.7) of severity equal or minor to 2, ME without clinical significance. Conclusions: The multidisciplinary system with well-established CPP detects 20.9 ME for 1,000 patients-day and intercepts 98.8% of ME with potential to damage the oncology patient.

No significant financial relationships to disclose.
Serial monitoring for circulating cancer cells in blood samples of stage 1–4 breast cancer patients
Authors: Tkaczuk K. H. , Tait N. S. , Chua K. , Feldman F. , Lesko S. A. , Lun Z. , Tan M. , Ts’o P. O.
Published: March 2020

623

Serial monitoring for presence, number & characterization of circulating cancer cells (CCC) may provide valuable information that may be relevant to prognosis and treatment outcomes of breast cancer patients (BCP). We conducted a serial blood sampling study at the University of Maryland in BCP with stage 1–4 breast carcinoma. 15–20 ml of venous blood were collected before the start of systemic therapy and periodically thereafter & processed using negative selection method with double-gradient centrifugation & magnetic cell sorting to remove WBCs. Digital images of FITC-positive epithelial cells were acquired with a fluorescence microscope & counted. CCC from 41 patients (Pts) were also stained with Trastuzu-mAb-532 to quantify the HER-2/neu cell surface receptor expression relative to a fluorescence standard. 105 Pts were accrued & 415 blood samples tested (median number of samples/pt; 4 (1–8). During the 24 mos. monitoring period CCC were detected in 57 of 105 pts (54%). The
Table
below shows that presence of >10 CCC/sample is associated with decreased survival and increased probability of having metastatic disease.(Exact chi-square test for presence vs. absence of metastatses in A, B, C, D groups, P < 0.0001; Fisher’s exact test to compare individual groups: for B vs C+ D, P < 0.001; B vs C, P=0.001). HER-2/neu expression was assessed in CCC of 25 pts (minimum of 4 CCC per sample) as compared with strongly HER-2/neu positive control cell line SKBR-3. 10 Pts were positive & 15 negative for HER-2/neu over-expression in CCC. CCC data & primary tumor data concurred in 6 of 7 Her-2/neu primary tumor tissue positive Pts & in 12 of 13 Her-2/neu primary tissue negative Pts. For 5 Pts tissue data was not available.
Conclusions:
Increasing CCC numbers/sample appear to correlate with adverse outcome of BCP. Our CCC Test may provide valuable information about prognosis of stage 1–4 BCP. HER-2/neu expression could be quantified in individual CCC & concurred with primary tumor data in 90% of Pts. Supported by NCI Grant CA081903

Patient Group
Number of CCC per sample
Patient Number
Death due to BC (%)
Absence of Metastatic Disease (%)

A

0
48
2 (4%)
45 (94%)

B

1–10
38
7 (18%)
18 (47%)

C

11–100
13
6 (46%)
1 (8%)

D

>100
6
5 (83%)
0

Author Disclosure

Employment or Leadership
Consultant or Advisory Role
Stock Ownership
Honoraria
Research Funding
Expert Testimony
Other Remuneration

CCC Diagnostics
CCC Diagnostics
Trastuzumab in adjuvant breast cancer therapy: A model based cost-effectiveness analysis
Authors: Norum J. , Olsen J. A.
Published: March 2020

628

Background: Trastuzumab has shown activity in patients with early breast cancer that overexpress HER2. However, significant resources have to be allocated to finance this therapy, therefore its cost-effectiveness is called for and treatment’s value for money should be calculated. We aimed to evaluate the marginal cost effectiveness of trastuzumab in adjuvant treatment of HER2 positive early breast cancer in a model based cost-effectiveness-analysis (CEA). Methods: A breast cancer treatment model was set up. Societal costs were calculated according to Norwegian prices as in September 2005 and converted to Euros at the rate of 1Euro = 7.81 NOK. Life expectancy data were based on the literature and prolonged according to qualified guess (10% and 20% improved overall survival (OS). The comparator was the present practice, the FEC100 regimen alone. The human capital approach was employed and a sensitivity analysis was added. Results: The median raised cost per patient treated was calculated at Euro16,713 - 35,714. The yielding cost per life year saved was in the range between Euro 5,571 and 32,616, depending on survival gain (10% or 20% improved OS) and discount rate (0% or 3%) employed. The sensitivity analyses documented survival gain, discount rate and price of trastuzumab the major factors influencing cost-effectiveness ratio. Conclusion: The economic evaluation indicates trastuzumab cost effective in adjuvant breast cancer treatment.

No significant financial relationships to disclose.
Long term cardiac tolerability of trastuzumab in HER-2-overexpressing metastatic breast cancer (MBC)
Authors: Guarneri V. , Lenihan D. J. , Valero V. , Durand J. , Broglio K. , Boehnke-Michaud L. , Gonzalez-Angulo A. M. , Hortobagyi G. N. , Esteva F. J.
Published: March 2020

629

Background: The use of trastuzumab is associated with an increased risk of cardiotoxic events such as congestive hearth failure (CHF) and decline in the left ventricular ejection fraction (LVEF). Our objectives were to evaluate the incidence of cardiac dysfunction, to identify risk factors and to evaluate the outcome of patients with MBC treated with trastuzumab for one year or longer. Methods: Among 218 MBC patients treated with trastuzumab-based therapy for at least one year, 173 patients were evaluable for cardiac toxicity. Cardiac events (CE) were defined as follows: 1) asymptomatic drop of LVEF below 50%; 2) drop of 20 percentage points in LVEF compared to the baseline; 3) signs or symptoms of CHF. The cardiac toxicity was graded according the NCI-CTCAE, version 3.0. Results: Median age at the start of trastuzumab therapy was 50 years (range, 26–79), median cumulative time on trastuzumab was 21.3 months (range, 11.6–77.6), and median follow-up was 32.2 months (range, 9.7–79.0). Eighty-five percent of patients received prior anthracyclines (median cumulative doxorubicin dose: 300 mg/m2). Forty-nine patients (28%) experienced a CE: 3 patients (1.7%) had an asymptomatic drop in the LVEF of 20 percentage points; 27 patients (15.6%) experienced grade 2 cardiac toxicity; and 18 patients (10.4%) experienced grade 3 cardiac toxicity. There was one cardiac related death (0.5%). Cardiac event-free survival was 87.3% at 1 year. All but four patients had improved LVEF or symptoms of CHF after stopping trastuzumab or with appropriate therapy. After complete recovery, 26 patients were re treated with trastuzumab; 16 patients did not experience further CE. Concomitant taxane use was the only factor significantly associated with a CE (HR: 4.37, 95%CI 1.06–17.98, p:0.04).Prior anthracycline exposure was not associated with increased risk of CE. Conclusions: The risk of cardiac toxicity of long-term trastuzumab-based therapy is acceptable in this population, and this toxicity is reversible in the majority of the patients. In patients who have experienced a CE, additional treatment with trastuzumab can be considered after recovery of cardiac function. The increased risk of cardiotoxicity associated with taxane administration needs to be further investigated.

No significant financial relationships to disclose.
Improved antitumor therapy by dual targeting of estrogen and growth factor receptor signaling in human breast cancer cells
Authors: Pietras R. J. , Marquez D. C. , Chen H. , Sliwkowski M. X. , Slamon D. J.
Published: March 2020

637

Background: Breast cancer growth is tightly regulated by interactions between growth factor and estrogen receptors. Dimerization is crucial for activation of HER receptors (EGFR, HER2, HER3, HER4) that contribute to modulation of tumor progression and the failure of antiestrogen therapy. HER2 is the preferred dimerization partner in a process stimulated by the several HER receptor ligands. HER2 antibody (trastuzumab) shows antitumor efficacy in HER2-overexpressing cancers. New antibodies that disrupt HER2 dimerization (pertuzumab) may be useful in treating cancers with normal HER2 levels. Methods: Estrogen receptor (ER)-positive tumor cells with normal HER levels (MCF-7, ZR75), as well as cells engineered for HER2-overexpression (MCF-7/HER2, ZR75/HER2) or tamoxifen resistance (MCF-7/TAM), were grown in vitro and as xenografts in nude mice and treated with tamoxifen, fulvestrant (Faslodex), trastuzumab or pertuzumab, alone or combined. Effects of agents on phosphorylation of ER and coactivator AIB1, ER-dependent transcripts, p27 and VEGF secretion were assessed. Results: Growth of ER-positive tumors with low HER is reduced by tamoxifen and fulvestrant. In contrast, HER2-overexpressing tumors are tamoxifen-resistant but retain sensitivity to fulvestrant and show greater, synergistic antitumor effects with trastuzumab-fulvestrant combined. Similarly, non-HER2-overexpressing tumors with or without tamoxifen resistance are sensitive to fulvestrant, but fulvestrant-pertuzumab elicits more profound antitumor effects (P<0.001). Enhanced inhibitory action of fulvestrant-pertuzumab is related, in part, to changes in phosphorylation of ER and AIB1, leading to blockade of ER-induced transcripts, as well as nuclear localization of p27, a CDK-inhibitor that downregulates cell proliferation. Further, enhanced tumor secretion of VEGF after estrogen and HER signaling is markedly reduced by fulvestrant-pertuzumab as compared with either agent alone (P<0.001). Conclusions: Pertuzumab promotes antitumor efficacy of the pure antiestrogen, fulvestrant, and dual disruption of ER and HER signaling may be a new way to optimize hormonal therapy and overcome antiestrogen resistance. Supported by US Army BCRP and Stiles Program.

[Table: see text]
Association between breast cancer and estrogen receptor gene polymorphism PVU II
Authors: Neuss K. , Elling D. , Cascorbi I. , Lueftner D.
Published: March 2020

643

Background: The estrogen receptor (ER) is well acknowledged as a prognostic factor in breast cancer, and it is a prerequisite to use the predictive information for hormonal therapy. We investigated whether that the different polymorphisms of the estrogen receptor could influence its expression or functionality. Methods: DNA was extracted from white blood cells of 236 breast cancer patients and 236 healthy, matched controls. The ER genotypes were determined by polymerase chain reaction (PCR) amplification followed by restriction enzyme digestion of the PCR product. Results were shown by electrophoreses. Clinical data such as histologic types, pTNM stage and patients age were available for statistical analyses. Results: We found a statistically significant correlation between the estrogen receptor polymorphism pattern and breast cancer. The receptor type PP was detected statistically significantly more often in postmenopausal breast cancer patients (PP vs pp+Pp, p =0.03). However, there was no correlation to the histobiochemical receptor status or UICC-Stadium. Conclusions: These results show an association between the estrogen receptor polymorphism and breast cancer. It seems to be that a complete lack of the p-allel is a risk factor to develop breast cancer at postmenopausal age. There was no influence on estrogen receptor expression or clinical tumor stage. Thus, we propose that there is no clinical use for estrogen receptor polymorphism analyses at this stage.

No significant financial relationships to disclose.
Tamoxifen discontinuance among women aged 65 years and older with estrogen receptor positive breast cancer
Authors: Owusu C. , Buist D. , Field T. , Lash T. L. , Thwin S. , Silliman R.
Published: March 2020

648

Background:
Five years ofadjuvant tamoxifen therapy in estrogen receptor (ER)-positive breast cancer is more effective than two years of use. However information on adjuvant tamoxifen therapy discontinuance is scanty. We aimed to identify predictors of tamoxifen discontinuance in older women with early stage breast cancer.
Methods:
Within six healthcare delivery systems, we identified 1080 women ≥65 years with stage I-IIb breast cancer diagnosed from 1990 to 1994 with ER-positive or indeterminate tumors who had been prescribed tamoxifen. We then followed them for five years post initial tamoxifen prescription. Data sources included tumor registries, administrative data, and medical records. We used automated pharmacy records to validate tamoxifen prescription information collected from medical records. The primary endpoint was tamoxifen discontinuance, operationalized as
ever
discontinuing tamoxifen during follow-up. We excluded women who discontinued tamoxifen due to recurrence, death or disenrollment from this definition. Independent variables included demographic characteristics, comorbidity, tumor characteristics, and primary therapy. We used Cox proportional hazards to determine predictors of tamoxifen discontinuance.
Results:
Of the 1080 women who were prescribed tamoxifen, 974 women did not have a recurrence, die or disenroll during follow-up. Of these 974 women, 489 (50%) stopped taking tamoxifen during the five years of follow-up. Discontinuers were more likely to be women aged 80 years and older (versus aged 65–69, hazard ratio (HR)= 1.96, 95% confidence interval (CI)=1.51–2.56); have a Charlson Comorbidity Index of 1 (versus a Charlson Comorbidity Index of 0, HR=1.31, CI=1.07–1.61); have indeterminate receptor status (versus ER-positive, HR=1.49, CI=1.12–2.00); and to have not received breast-conserving surgery with radiation therapy or mastectomy (HR=1.37, CI=1.10–1.71).
Conclusion:
Attention to non-adherence among women at risk of discontinuance, particularly not receiving guideline care, might improve breast cancer outcomes for these women.

No significant financial relationships to disclose.
Clinical outcomes and rates of molecular remission with all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) combination therapy in newly diagnosed acute promyelocytic leukemia (APL)
Authors: Tsimberidou A. M. , Kantarjian H. M. , Garcia-Manero G. , Koller C. , Jones D. M. , Keating M. J. , Estey E.
Published: March 2020

6503

Background: ATRA and anthracyclines provide durable remissions in patients with untreated APL. As2O 3 has improved outcomes in untreated and relapsed/refractory APL. The aim of this study was to determine the rates of complete response (CR) and molecular remission with ATRA and As2O 3 combination therapy in untreated APL. Methods: From 2/02 to 1/06, 53 patients with untreated APL received ATRA 45 mg/m2 daily and As2O 3 0.15 mg/kg IV 1-hr infusion daily starting on day 10. Patients with WBC>10×109/L also received gemtuzumab ozogamicin (GO) 9 mg/m2 on day 1 and/or idarubicin 12 mg/m2 on days 1–4. Patients in CR received As2O 3 0.15 mg/kg IV on days 1–5 weekly for 4 weeks on and 4 weeks off and ATRA 45 mg/m2 daily for 2 weeks on and 2 weeks off (for 28 weeks). Polymerase chain reaction (PCR) testing for PML-RARα (sensitivity level, 10−4) was performed every 3 months from CR for 2 years. Patients with molecular relapse received GO 9 mg/m2 once monthly for 3 months in addition to ATRA and As2O 3 as in postremission therapy. If PCR became negative, only the single dose of GO was given. Results: The median age was 46 years; and 20% of patients were Sanz low risk, 40% intermediate, and 40% high risk. The CR rate was 91% (low risk 91%, intermediate 95%, high risk 86%). The median follow-up in surviving patients was 1.6 years. Six patients died during induction, and 2 died in CR from other cancers. The 1-yr survival rate was 88%. Three patients relapsed (at 9, 9, and 16 months). The 1-yr failure-free survival (FFS) rate in responding patients was 94% (high risk 86%, other risk 100%). Molecular remission rates are shown in the Table . Grade 3–4 nonhematologic toxicities were infections (n=16), neurologic (n=4), cardiac arrhythmias (n=4), APL differentiation syndrome (n=4), and headache (n=2). Conclusions: ATRA plus As2O 3 results in high rates of CR, molecular remission, FFS, and survival and is an alternative to ATRA and idarubicin combination therapy in low-risk APL.

[Table: see text]

No significant financial relationships to disclose.
PML-RARα isoform at diagnosis is associated with disease-free survival (DFS) in patients enrolled in the intergroup trial (C-9710) for treatment of acute promyelocytic leukemia (APL)
Authors: Stock W. , Moser B. , Sher D. A. , Schachter-Tokarz E. , Myers M. , Powell B. L. , Bloomfield C. D. , Bucci D. , Tallman M. S. , Larson R. A. , Gallagher R. E.
Published: March 2020

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Background: Refinement of prognostic groups using molecular genetic features of the disease may facilitate the design of future risk-adapted trials for APL. Previous analyses of the prognostic value of PML-RARα transcript levels and isoform type have generated conflicting results. We sought to determine the clinical significance of measuring PML-RARα transcript level at the time of diagnosis using real-time quantitative RT-PCR (RQ-PCR) of the long (L) and short (S) isoforms of the fusion gene. Methods: PML-RARα transcript levels were measured in pretreatment bone marrow (BM) and/or paired blood (B) samples of 139 patients (pts) with newly diagnosed APL registered to C-9710, the intergroup phase III randomized study of concurrent tretinoin and chemotherapy with or without arsenic trioxide as initial consolidation therapy. Transcript levels were expressed as the normalized quotient (NQ) of PML-RARα/ABL or PML-RARα/GAPDH. Correlations between pre-treatment NQ values and other pre-treatment characteristics including age, presenting WBC and platelet count, and L or S isoform were explored. Results: Pre-treatment NQ values using ABL vs. GAPDH showed significant correlation (p < 0.0001). Pre-treatment transcript levels in B and BM for 57 pts with S-form were significantly higher than 82 L-form patients (p = 0.02) when NQ was determined using GAPDH as the control gene (but not with ABL). With a median follow-up of 24.3 months for all patients, there have been 19 events. Median DFS for either isoform has not been reached, however, DFS was significantly shorter for patients with S-isoform compared to those with L-isoform (p = 0.017) with an estimated hazard ratio of 3.28. Using a multivariate proportional hazard model, no other significant relationships were found between DFS and NQ level at diagnosis, age, presenting WBC or platelet count. Conclusions: The S-isoform of the PML-RARa fusion gene was associated with shorter DFS in a subset of patients entered onto C-9710. If confirmed in a larger cohort of C-9710 pts, presence of the S-isoform should be considered as a high-risk feature in the design of future risk-adapted treatment strategies for APL.

No significant financial relationships to disclose.
Preliminary phase III efficacy and safety of alemtuzumab vs chlorambucil as front-line therapy for patients with progressive B-cell chronic lymphocytic leukemia (BCLL)
Authors: Hillmen P. , Skotnicki A. , Robak T. , Jaksic B. , Dmoszynska A. , Sirard C. , Mayer J.
Published: March 2020

6511

Background: Phase 3, open-label, randomized comparative trial, enrolled Rai stage I-IV BCLL patients with previously untreated, progressive disease requiring treatment. Objectives: Compare efficacy and safety of alemtuzumab (CAMPATH [(CAM]) to chlorambucil (CHLO) as front-line therapy. Methods:Patients were randomized 1:1 to CAM 30 mg IV 3x/week for a maximum of 12 weeks (wks) or CHLO 40 mg/m2 PO once every 28 days, to a maximum of 12 cycles. All CAM patients received prophylactic antibiotic (trimethoprim/sulfamethoxazole DS) and antiviral (famciclovir) treatment during therapy and until CD4+ counts were ≥200 cells/μL. The primary endpoint was progression free survival; secondary endpoints included safety, response rate and overall survival. Results: Accrual completed in July 2004 with 297 patients enrolled (213 males, 84 females; median age 60 years); CAM n=149 and CHLO n=148. Treatment arms were balanced for key prognostic factors analyzed to date. Most patients had performance status 0–1 (96%) and maximum lymph nodes <5cm (70%). Median length of treatment with CAM = 11.7 wks, CHLO = 24.4 wks. The design provided for investigator assessment and an independent review of response (IRR). Preliminary data from the IRR are presented. Response rate for CHLO was consistent with historical data. Safety data indicate 34.7% of CAM patients and 19.7% of CHLO patients experienced a serious adverse event, with 21.1% and 4.1% considered drug related, respectively. The incidence of grade 3/4 thrombocytopenia and anemia were comparable in both treatment arms. Grade 3/4 neutropenia (42.2% vs 23.1%), infections (excluding CMV) (14.3% vs 6.8%), and CMV infections (6.8% vs 0%) were more frequent in the CAM arm. One treatment related death occurred in the CHLO arm. Conclusions: Preliminary efficacy and safety data confirm therapy naïve BCLL patients treated with single agent CAM have an excellent response rate with a manageable toxicity profile.

[Table: see text]

[Table: see text]
Cloretazine is an effective induction therapy in elderly patients (pts) with poor-risk de novo AML
Authors: Karp J. E. , Rizzieri D. , Vey N. , Mufti G. , Geller R. , O’Brien S. , Giles F.
Published: March 2020

6512

Background: The incidence of AML increases with age with a median of 68 years in the US. The treatment of elderly pts (≥60 years) with AML poses challenges related to pt characteristics (age, performance status (PS), comorbidities) and adverse biological features. The majority of elderly pts are not considered for standard induction therapies that incorporate araC + anthracycline, and complete remission rates (CR+CRp), leukemia-free (LFS) and overall survival (OS) are significantly lower than in younger pts. As a result, NCCN guidelines recommend investigational therapy for this population. Cloretazine (C) is a novel DNA alkylating agent that selectively targets the O-6 position in guanine and has been developed in AML, based on phase I data demonstrating activity in refractory hematologic malignancies with acceptable toxicity. Methods: A multi-center trial in elderly pts with untreated poor-risk AML and high risk MDS was performed. Pts received C (600 mg/m2) as a single 30–60 minute infusion. Retreatment for induction was permitted for pts who showed improvement. A consolidation course of C at 400 mg/m2 was an option for pts who achieved a CR. Results: 105 pts were treated, of whom 45 pts (median age 72, range 60–84) had de novo AML, 44 had secondary AML, and 16 had high-risk MDS. Considering only de novo AML pts, pt characteristics are the following: M/F=25/20; favorable/intermediate/poor/NA cytogenetics =0/28(62%)/15(33%)/2; and PS 0/1/2=8(18%)/21(47%)/16(36%). The CR rate was 49% (N=22). CR was 50% for pts with intermediate cytogenetics and 53% for pts with poor risk cytogenetics. CR remained consistent despite increasing PS (PS0=50%, PS1=48%, PS2=50%). For responders, the median time for ANC≥1000 cells/dl was 31 days (range 27–44) and for plt≥20,000/dl was 22 days (range 14–29). There was no significant non-hematologic toxicity; the early death rate was 20%. Of the 22 pts who achieved CR, 8 remain alive and disease-free at a median of 337 days (range 137–546). At one year, the LFS is 27% and the OS is 22%. Conclusion: C is very well tolerated and has demonstrated impressive response results as a single agent in an elderly pt population with poor risk AML.

[Table: see text]
Expression signature of p53 status (p53 signature) for the prediction of TP53 mutation and prognosis in breast cancer
Authors: Ishioka C. , Takahashi S. , Ishida T. , Moriya T. , Ohuchi N.
Published: March 2020

652

Background: The current risk evaluation criteria, such as the St. Gallen and NIH, are not sufficient for predicting which BC patients are at high risk for recurrence and mortality. The TP53 mutations are associated with worse RFS and OS, independent other risk factors in BC, but the p53 status is not simply determined and often determined incorrectly (Soussi et al. Nat Rev Cancer 2006). Our purpose was to identify the gene sets that determine expression signature of the p53 status and to correlate the gene expression profile (GEP) with clinical outcome. Methods: Comprehensive expression analysis (Agilent 41K human genome oligo microarray) and DNA sequencing of the TP53 gene in 38 Japanese BC (30 Stage I-II, 8 stage III-IV; 20 TP53 wt, 20 TP53 mt) were performed using RNA and DNA obtained from the microdissected frozen tumor samples. We determined a gene set consisted of 33 genes from differentially expressed genes depending on the p53 status in the 26 BC (training set) and validated the ability to predict p53 status in the remaining 12 BC (test set). Prognostic value of the gene set was analyzed in 29 BC (stage I or II), and were validated using publicly available dataset of the independent 295 BC (stage I or II), van de Vijver et al. NEJM 2002). Results: The GEP using the 33 genes, many of which related in cell cycle and cell division, predicted the p53 status (wt or mt p53 signature) accurately in the test set (accuracy: 83%, overall accuracy: 95%). The p53 signature has the ability to predict RFS of the 29 early BC (Log Rank, P=0.032). It divided the 295 early BC into 176 wt and 119 mt group, and also has the ability to predict both RFS and OS (Log Rank, both P<0.0001). This was also true when the cohort were stratified by ER status, LN status, St. Gallen criteria and NIH criteria, and retained the predicted value in ER+, LN+, LN-, St. Gallen (intermediate/high) and NIH (high) subgroups (Log Rank, P<0.0001). Conclusions: The p53 signature is a powerful and independent predictor of the outcome of disease in early breast cancer than standard systems based on clinical and histologic criteria.

No significant financial relationships to disclose.