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Kaplan H.G.,Swedish Medical Center | Malmgren J.A.,HealthStat Consulting Inc. | Malmgren J.A.,University of Washington | Atwood M.,Swedish Medical Center | Goldstein L.C.,PhenoPath Laboratories
Cancer Management and Research | Year: 2010

Purpose: Human epidermal growth factor receptor 2 (HER2)/neu, topoisomerase II alpha (TOP2A), and polysomy 17 may predict tumor responsiveness to doxorubicin (DOX) therapy. Methods: We identified neoadjuvant DOX/cyclophosphamide treated breast cancer patients in our registry from 1997 to 2008 with sufficient tissue for testing (n = 34). Fluorescence in situ hybridization (FISH) testing was done on deparaffinized tissue sections pretreated using vendor's standard protocol modification, and incubated with US Food and Drug Administration approved Abbott Diagnostics Vysis PathVysion TM probe set, including Spectrum-Green-conjugated probe to α-satellite DNA located at the centromere of chromosome 17 (17p11.1-q11.1) and a Spectrum-Orange-conjugated probe to the TOP2A gene. Morphometric analysis was performed using a MetaSystems image analysis system. Manual counting was performed on all samples in which autofluorescence and/or artifact prevented the counting of sufficient numbers of cells. A ratio. >2.0 was considered positive for TOP2A amplification. Polysomy 17 (PS17) presence was defined as signals of ≥2.5. Outcomes were pathological complete response (pCR), partial response (PR), and nonresponse (NR). Results: Of 34 patients tested, one was TOP2A amplified (hormone receptor negative/HER2 negative, partial responder). The subset of TOP2A nonamplified, HER2 negative, and PS17 absent (n = 23) patients had treatment response: pCR = 2 (9%), PR = 14 (61%), and NR = 7 (30%). Including the two PS17 present and HER2-positive patients (n = 33), 76% of TOP2A nonamplified patients had pCR or PR. Conclusions: We observed substantial treatment response in patients lacking three postulated predictors that would be difficult to attribute to cyclophosphamide alone. Patients who are HER2 negative and lack TOP2A amplification and PS17 should not be excluded from receiving DOX-containing regimens.©2010 Kaplan et al, publisher and licensee Dove Medical Press Ltd.

Kaplan H.G.,Swedish Cancer Institute | Malmgren J.A.,HealthStat Consulting Inc. | Malmgren J.A.,University of Washington | Atwood M.K.,Swedish Cancer Institute
Journal of Geriatric Oncology | Year: 2013

Objective: To assess adjuvant chemotherapy recommendations, administration and disease-specific survival for invasive breast cancer (BC) among patients 75. years and older compared with that of younger women. Materials and Methods: A cohort of patients with primary breast cancer, aged 65-94, stages I-III from 1990 to 2010 was identified and tracked by our breast cancer registry (n. =2329). Stage, treatment recommendations and outcomes were chart abstracted at diagnosis and follow-up. Associations were tested with logistic regression and the Kaplan-Meier method was used for disease-specific survival (DSS). Results: Seventy-five percent of patients aged 75. + were seen by an oncologist compared with 78% aged 70-74 and 84% aged 65-69. Women aged 75. + seen by an oncologist were more likely age 75-79, stage II/III, hormone receptor negative (HR. -) or her-2/neu positive. Of these patients, age, stage and HR status were related to a chemotherapy recommendation. Of 106 patients recommended for chemotherapy, 18 refused (17%) and 24 did not complete treatment due to complications, patient choice, disease progression or death not related to treatment. DSS was equivalent for patients 75 and older with stage I BC compared to 65-74. year olds, but significantly worse in stage II and III patients, respectively (stage II 5. year DSS 90% vs. 97%, stage III 5. year DSS 65% vs. 81%). Conclusion: Patients aged 75 and older with invasive breast cancer who were recommended for adjuvant chemotherapy have a high rate of refusal and complications from therapy. Their disease specific mortality disadvantage is restricted to stage II and III patients, a group in need of effective therapy to improve disease survival. © 2013 Elsevier Inc.

Malmgren J.A.,HealthStat Consulting Inc. | Malmgren J.A.,University of Washington | Calip G.S.,University of Illinois at Chicago | Pyott S.M.,PhenoPath Laboratories | And 2 more authors.
Leukemia Research | Year: 2016

Background Therapy-related myelodysplastic syndrome (t-MDS) is a serious clinical disease occurring after breast cancer treatment. Methods A cohort of 11,684 invasive breast cancer (BC) patients from 1990–2014 were followed for incidence of t-MDS through institutional and the Surveillance, Epidemiology and End Results (SEER) Program registries. t-MDS cases were identified using ICD-O SEER registry codes, pathology and chart reports. Treatment, cytogenetics, and time from BC diagnosis to t-MDS and t-MDS diagnosis to last follow up or death were obtained. Incidence rate ratios were calculated using SEER national incidence rates for comparison. Results 27 cases of t-MDS post BC treatment were confirmed. 96% of cases were breast cancer stage I–II at diagnosis. All patients had received radiation treatment and 59% received adjuvant chemotherapy. Two patients were alive with no evidence of disease after treatment with stem cell transplantation (age 33 and 46). t-MDS incidence was 30 times the expected population rate among patients <55 years (RR 31.8, 95% CI 15.0, 60.8) with shorter time from t-MDS diagnosis to death (median survival time: <55: 8 months, 55–74: 26 months, 75+: 23 months). Conclusion We found elevated t-MDS risk especially among younger BC patients with stem cell transplantation the only observed curative treatment. © 2016 Elsevier Ltd

Kaplan H.G.,Swedish Medical Center | Malmgren J.A.,HealthStat Consulting Inc. | Malmgren J.A.,University of Washington | Atwood M.K.,Swedish Medical Center
BMC Cancer | Year: 2011

Background: Our objective was to measure myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) risk associated with radiation and/or chemotherapy breast cancer (BC) treatment.Methods: Our study cohort was composed of BC patients diagnosed from 1990 to 2005 and followed up for blood disorders, mean length of follow up = 7.17 years, range 2-18 years. 5790 TNM stage 0-III patients treated with surgery alone, radiation and/or chemotherapy were included. Patients without surgery (n = 111), with stem cell transplantation (n = 98), unknown or non-standard chemotherapy regimens (n = 94), lost to follow up (n = 66) or 'cancer status unknown' (n = 67) were excluded. Rates observed at our community based cancer care institution were compared to SEER incidence data for rate ratio (RR) calculations.Results: 17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period, crude rate .29% (95% CI = .17, .47), SEER comparison RR = 3.94 (95% CI = 2.34, 6.15). The RR of MDS in patients age < 65 comparing our cohort incidence to SEER incidence data was 10.88 (95% CI = 3.84, 24.03) and the RR of AML in patients age < 65 was 5.32 (95% CI = 1.31, 14.04). No significant increased risk of MDS or AML was observed in women ≥ 65 or the surgery/chemotherapy-only group. A RR of 3.32 (95% CI = 1.42, 6.45) was observed in the surgery/radiation-only group and a RR of 6.32 (95% CI = 3.03, 11.45) in the surgery/radiation/chemotherapy group. 3 out of 10 MDS cases died of disease at an average 3.8 months post diagnosis and five of seven AML cases died at an average 9 months post diagnosis.Conclusions: An elevated rate of MDS and AML was observed among breast cancer patients < 65, those treated with radiation and those treated with radiation and chemotherapy compared to available population incidence data. Although a small number of patients are affected, leukemia risk associated with treatment and younger age is significant. © 2011 Kaplan et al; licensee BioMed Central Ltd.

Calip G.S.,University of Illinois at Chicago | Calip G.S.,Fred Hutchinson Cancer Research Center | Calip G.S.,University of Washington | Malmgren J.A.,University of Washington | And 5 more authors.
Breast Cancer Research and Treatment | Year: 2015

Risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) post-breast cancer treatment with adjuvant chemotherapy and granulocyte colony-stimulating factors (G-CSF) is not fully characterized. Our objective was to estimate MDS/AML risk associated with specific breast cancer treatments. We conducted a retrospective cohort study of women aged ≥66 years with stage I–III breast cancer between 2001 and 2009 using the Surveillance, Epidemiology, and End Results-Medicare database. Women were classified as receiving treatment with radiation, chemotherapy, and/or G-CSF. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95 % confidence intervals (CI) for MDS/AML risk. Among 56,251 breast cancer cases, 1.2 % developed MDS/AML during median follow-up of 3.2 years. 47.1 % of women received radiation and 14.3 % received chemotherapy. Compared to breast cancer cases treated with surgery alone, those treated with chemotherapy (HR = 1.38, 95 %-CI 0.98–1.93) and chemotherapy/radiation (HR = 1.77, 95 %-CI 1.25–2.51) had increased risk of MDS/AML, but not radiation alone (HR = 1.08, 95 % CI 0.86–1.36). Among chemotherapy regimens and G-CSF, MDS/AML risk was differentially associated with anthracycline/cyclophosphamide-containing regimens (HR = 1.86, 95 %-CI 1.33–2.61) and filgrastim (HR = 1.47, 95 %-CI 1.05–2.06), but not pegfilgrastim (HR = 1.10, 95 %-CI 0.73–1.66). We observed increased MDS/AML risk among older breast cancer survivors treated with anthracycline/cyclophosphamide chemotherapy that was enhanced by G-CSF. Although small, this risk warrants consideration when determining adjuvant chemotherapy and neutropenia prophylaxis for breast cancer patients. © 2015, Springer Science+Business Media New York.

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