George W. Sledge Jr., M.D.
Adjunct Clinical Professor, Medicine - Oncology
Clinical Focus
- Cancer
- Cancer > Breast Cancer
- Medical Oncology
Administrative Appointments
-
Chief, Division of Oncology, Department of Medicine (2013 - 2020)
-
Professor, Medicine (2013 - Present)
Honors & Awards
-
Ballve-Lantero Chair (Endowed Chair), Ballve-Lantero (1996)
-
Editor-In-Chief, Clinical Breast Cancer (1999-present)
-
Listed in "America's Top Doctors", Castle Connolly (2001-2012)
-
Chair, Breast Committee, Eastern Cooperative Oncology Group (ECOG) (2002-2010)
-
Komen Brinker Award for Scientific Distinction, Susan G. Komen Breast Cancer Foundation (2006)
-
Jill Rose Award, Breast Cancer Foundation (2007)
-
William L. McGuire Award, San Antonio Breast Cancer Symposium (2010)
-
President, American Society of Clinical Oncology, American Society of Clinical Oncology (ASCO) (2010-2011)
-
Health Care Hero award, Indianapolis Business Journal (2011)
-
APEX Award for Publication Excellence in the category of "Regular Departments & Columns", Oncology Times (2012)
-
Gianni Bonnadona Award for Breast Cancer Research, American Society of Clinical Oncology (2020)
-
HOPE Funds for Cancer Research 2013 Award of Excellence for Medicine, HOPE Funds, Cancer Research (April 28, 2013)
Professional Education
-
Medical Education: Tulane University School of Medicine (1977) LA
-
Fellowship: University of Texas at San Antonio (1983) TX
-
Board Certification: American Board of Internal Medicine, Medical Oncology (1983)
-
Board Certification: American Board of Internal Medicine, Internal Medicine (1980)
-
Residency: St Louis University Hospital (1980) MO
Clinical Trials
-
4-1BB Agonist Monoclonal Antibody PF-05082566 With Trastuzumab Emtansine or Trastuzumab in Treating Patients With Advanced HER2-Positive Breast Cancer
Not Recruiting
This trial studies the best dose and side effects of utomilumab (4-1BB agonist monoclonal antibody PF-05082566) with trastuzumab emtansine or trastuzumab in treating patients with HER2-positive breast cancer that has spread to other places in the body. Monoclonal antibodies, such as utomilumab, trastuzumab emtansine, and trastuzumab may interfere with the ability of tumor cells to grow and spread.
Stanford is currently not accepting patients for this trial. For more information, please contact Oshra Sedan, 650-723-0628.
-
A Phase 1/2 Study of MEDI4276 in Adults Subjects With Select HER2-expressing Advanced Solid Tumors.
Not Recruiting
This research study is designed to evaluate an experimental drug, MEDI4276, in treating breast and stomach (gastric) cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)
Not Recruiting
The purpose of this 2-stage, 2-cohort Phase 2 trial is to evaluate the safety and efficacy of talazoparib (also known as BMN 673) in subjects with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. Subjects will be assigned to either Cohort 1 or 2 based on prior chemotherapy for metastatic disease: * Cohort 1) Subjects with a documented PR or CR to a prior platinum-containing regimen for metastatic disease with disease progression \> 8 weeks following the last dose of platinum; or * Cohort 2) Subjects who have received \> 2 prior chemotherapy regimens for metastatic disease and who have had no prior platinum therapy for metastatic disease
Stanford is currently not accepting patients for this trial. For more information, please contact Karen Lau, 650-723-0658.
-
A Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer
Not Recruiting
A Clinical Trial of PM01183 in Metastatic Breast Cancer to assess the antitumor activity of PM01183 ,to evaluate whether the presence of a known germline mutation in BRCA 1/2 predicts response to PM01183 in Metastatic Breast Cancer (MBC) patients, to evaluate the safety profile of this PM01183 to analyze the pharmacokinetics (PK) and PK/PD (pharmacokinetic/pharmacodynamic) correlations and to evaluate the pharmacogenomic (PGx) expression profile in tumor samples.
Stanford is currently not accepting patients for this trial. For more information, please contact Pei-Jen Chang, 650-725-0866.
-
A Study Evaluating Safety and Efficacy of the Addition of ABT-888 Plus Carboplatin Versus the Addition of Carboplatin to Standard Chemotherapy Versus Standard Chemotherapy in Subjects With Early Stage Triple Negative Breast Cancer
Not Recruiting
This is a 3 arm Phase 3 study to evaluate the safety and efficacy of the addition of veliparib plus carboplatin versus the addition of carboplatin to standard neoadjuvant chemotherapy versus standard neoadjuvant chemotherapy in subjects with early stage TNBC.
Stanford is currently not accepting patients for this trial. For more information, please contact Pei Jen Chang, 650-725-0866.
-
A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)
Not Recruiting
The purpose of this open-label, 2:1 randomized phase III trial is to compare the safety and efficacy of talazoparib (also known as BMN 673) versus protocol-specific physician's choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
A Study Evaluating The PF-03084014 In Combination With Docetaxel In Patients With Advanced Breast Cancer
Not Recruiting
This study is aimed to determine the tolerability of the PF-03084014 plus docetaxel combination in patients with advanced breast cancer. Preliminary information about the efficacy of the combination will also be collected.
Stanford is currently not accepting patients for this trial. For more information, please contact Karen Lau, 650-723-0658.
-
A Study of Abemaciclib (LY2835219) Combined With Fulvestrant in Women With Hormone Receptor Positive HER2 Negative Breast Cancer
Not Recruiting
The main purpose of this study is to compare progression-free survival for women with hormone receptor positive (HR+), human epidermal growth factor receptor (HER2) negative advanced breast cancer receiving either abemaciclib + fulvestrant or fulvestrant alone. Participants will be randomized to abemaciclib or placebo in a 2:1 ratio. The study will last about 9 months for each participant. For the endocrine naïve cohort, all participants will received abemaciclib + fulvestrant.
Stanford is currently not accepting patients for this trial. For more information, please contact Annabel Castaneda, 650-498-7977.
-
A Study of ABT-165 in Subjects With Solid Tumors
Not Recruiting
This is a Phase 1/1b open-label study evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of ABT-165 when administered as monotherapy and in combination with paclitaxel or 5-fluoruracil, folinic acid and irinotecan (FOLFIRI) or ABBV-181 with/without paclitaxel in subjects with advanced solid tumors. Enrollment to Cohorts A, B were completed and for Cohorts C and D are recruiting.
Stanford is currently not accepting patients for this trial. For more information, please contact Janet Pan, 650-723-0628.
-
A Study of Atezolizumab and Paclitaxel Versus Placebo and Paclitaxel in Participants With Previously Untreated Locally Advanced or Metastatic Triple Negative Breast Cancer (TNBC)
Not Recruiting
This Phase 3, multicenter, randomized, double-blind, placebo controlled study is designed to evaluate the efficacy and safety of atezolizumab (MPDL3280A, an anti-programmed death-ligand 1 \[PD-L1\] antibody) administered in combination with paclitaxel compared with placebo in combination with paclitaxel in participants with previously untreated, inoperable locally advanced or metastatic, centrally confirmed TNBC. Participants will be randomized in a 2:1 ratio to receive atezolizumab or placebo plus paclitaxel until disease progression or unacceptable toxicity or end of study, whichever occurs first (maximum up to approximately 40 months). In addition, the Sponsor may decide to terminate the study at any time.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
A Study of Atezolizumab in Combination With Nab-Paclitaxel Compared With Placebo With Nab-Paclitaxel for Participants With Previously Untreated Metastatic Triple-Negative Breast Cancer (IMpassion130)
Not Recruiting
This multicenter, randomized, double-blind study evaluated the efficacy, safety, and pharmacokinetics of atezolizumab (MPDL3280A) administered with nab-paclitaxel compared with placebo in combination with nab-paclitaxel in participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not received prior systemic therapy for metastatic breast cancer (mBC). The safety of single-agent nab-paclitaxel has been determined in previous studies of participants with mBC and the safety data to date suggest that atezolizumab can be safely combined with standard chemotherapy agents.
Stanford is currently not accepting patients for this trial. For more information, please contact Janet Pan, 650-723-0628.
-
A Study to Investigate Atezolizumab and Chemotherapy Compared With Placebo and Chemotherapy in the Neoadjuvant Setting in Participants With Early Stage Triple Negative Breast Cancer
Not Recruiting
This is a global Phase III, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of neoadjuvant treatment with atezolizumab (anti-programmed death-ligand 1 \[anti-PD-L1\] antibody) and nab-paclitaxel followed by doxorubicin and cyclophosphamide (nab-pac-AC), or placebo and nab-pac-AC in participants eligible for surgery with initial clinically assessed triple-negative breast cancer (TNBC).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer
Not Recruiting
A phase III multi-center, randomized, open-label trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with HR+/HER2- Early Breast Cancer (EBC)
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer
Not Recruiting
This randomized phase III trial studies how well doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel with or without carboplatin work in treating patients with triple-negative breast cancer. Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether doxorubicin hydrochloride and cyclophosphamide is more effective when followed by paclitaxel alone or paclitaxel and carboplatin in treating triple-negative breast cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Amy Isaacson, 650-723-0501.
-
Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer
Not Recruiting
Olaparib treatment in patients with germline BRCA1/2 mutations and high risk HER2 negative primary breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy
Stanford is currently not accepting patients for this trial. For more information, please contact Amy Isaacson, 650-723-0501.
-
Phase II Trial of Talazoparib in BRCA1/2 Wild-type HER2-negative Breast Cancer and Other Solid Tumors
Not Recruiting
The aim of this single-arm phase 2 clinical trial is to evaluate the anti-cancer activity of Talazoparib (also known as BMN 673) in patients with advanced breast cancer with specific genetic or tumor genomic alterations. Patients with either triple-negative or HER2-negative breast cancer are eligible.
Stanford is currently not accepting patients for this trial. For more information, please contact Pei Jen Chang, 650-725-0866.
-
Study of Infigratinib in Combination With Tamoxifen in Hormone Receptor Positive, HER2 Negative, FGFR Altered Advanced Breast Cancer
Not Recruiting
The purpose of the study is identify the dose(s) of infigratinib to use in combination with tamoxifen to treat patients with a particular type of advanced breast cancer (hormone receptor-positive, HER2-negative, FGFR-altered breast cancer)
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Kody, 650-498-8583.
-
The IDEA Study (Individualized Decisions for Endocrine Therapy Alone)
Not Recruiting
This study will collect rates of local/regional recurrence in select patients who do not receive radiation treatment after lumpectomy surgery. These women must be postmenopausal; have hormone receptor-positive, Her2-negative tumors; have Oncotype-DX RS less than or equal to 18; and plan to receive endocrine therapy. In this way, this study seeks to collect prospective data supporting the idea that this is a population at sufficiently low risk of local/regional recurrence that omission of adjuvant radiation might be a reasonable option.
Stanford is currently not accepting patients for this trial.
All Publications
-
The Project Baseline Health Study: a step towards a broader mission to map human health
NPJ DIGITAL MEDICINE
2020; 3 (1): 84
Abstract
The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.
View details for DOI 10.1038/s41746-020-0290-y
View details for Web of Science ID 000538242900001
View details for PubMedID 32550652
View details for PubMedCentralID PMC7275087
-
Linking insurance claims across time to characterize treatment, monitoring, and end-of-life care in metastatic breast cancer.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303141
-
Early discontinuation to adjuvant endocrine therapy in the ECOG-ACRIN TAILORx Trial.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303089
-
MONARCH 2: Subgroup analysis of patients receiving abemaciclib plus fulvestrant as first- and second-line therapy for HR+, HER2-advanced breast cancer.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368300282
-
Monarch 2: Interim Overall Survival of Abemaciclib Plus Fulvestrant in Patients with HR+, HER2-Advanced Breast Cancer
KARGER. 2020: 15
View details for Web of Science ID 000517158700040
-
Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy.
The oncologist
2020; 25 (2): e243-e251
Abstract
In the phase III MONARCH 2 study (NCT02107703), abemaciclib plus fulvestrant significantly improved progression-free survival (PFS) versus placebo plus fulvestrant in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). This study assessed patient-reported pain, global health-related quality of life (HRQoL), functioning, and symptoms.Abemaciclib or placebo (150 p.o. mg twice daily) plus fulvestrant (500 mg, per label) were randomly assigned (2:1). The modified Brief Pain Inventory, Short Form (mBPI-sf); European Organization for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30); and Breast Cancer Questionnaire (QLQ-BR23) assessed outcomes. Data were collected at baseline, cycle 2, every two cycles 3-13, thereafter at every three cycles, and 30 days postdiscontinuation. Longitudinal mixed regression and Cox proportional hazards models assessed postbaseline change and time to sustained deterioration (TTSD) by study arm.On-treatment HRQoL scores were consistently maintained from baseline and similar between arms. Patients in the abemaciclib arm (n = 446) experienced a 4.9-month delay in pain deterioration (mBPI-sf), compared with the control arm (n = 223), and significantly greater TTSD on the mBPI-sf and analgesic use (hazard ratio, 0.76; 95% CI, 0.59-0.98) and QLQ-C30 pain item (hazard ratio, 0.62; 95% CI, 0.48-0.79). TTSD for functioning and most symptoms significantly favored the abemaciclib arm, including fatigue, nausea and vomiting, and cognitive and social functioning. Only diarrhea significantly favored the control arm (hazard ratio, 1.60; 95% CI, 1.20-2.10).HRQoL was maintained on abemaciclib plus fulvestrant. Alongside superior PFS and manageable safety profile, results support treatment with abemaciclib plus fulvestrant in a population of patients with endocrine-resistant HR+, HER2-negative ABC.In MONARCH 2, abemaciclib plus fulvestrant demonstrated superior efficacy and a manageable safety profile for patients with in hormone receptor-positive (HR+), HER2-negative (-) advanced breast cancer (ABC). Impact on health-related quality of life (HRQoL) is important to consider, given the palliative nature of ABC treatment. In this study, abemaciclib plus fulvestrant, compared with placebo plus fulvestrant, significantly delayed sustained deterioration of pain and other patient-reported symptoms (including fatigue, nausea, vomiting), and social and cognitive functioning. Combined with demonstrated clinical benefit and tolerability, the stabilization of patient-reported symptoms and HRQoL further supports abemaciclib plus fulvestrant as a desirable treatment option in endocrine resistant, HR+, HER2- ABC.
View details for DOI 10.1634/theoncologist.2019-0551
View details for PubMedID 32043763
-
Impact of insurance and socioeconomic status on clinical outcomes in therapeutic clinical trials for breast cancer
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7445.SABCS19-PD10-09
View details for Web of Science ID 000527012503270
-
Safety and efficacy of abemaciclib plus endocrine therapy (ET) in elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+, HER2-) advanced breast cancer: An age-specific subgroup analysis of MONARCH 2 and 3 trials
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7445.SABCS19-P1-19-10
View details for Web of Science ID 000527012500331
-
Clinical Significance of PIK3CA and ESR1 Mutations in CTDNA and FFPE Samples from The Monarch2 Study of Abemaciclib Plus Fulvestrant
KARGER. 2020: 9–10
View details for Web of Science ID 000517158700026
-
MONARCH 2: Interim analysis of overall survival in patients with poor prognostic factors
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7445.SABCS19-P3-08-01
View details for Web of Science ID 000527012501308
-
Patient familiarity with, understanding of, and preferences for clinical trial endpoints and terminology.
Cancer
2020
Abstract
BACKGROUND: Although there is increased attention to designing and explaining clinical trials in ways that are clinically meaningful for patients, there is limited information on patient preferences, understanding, and perceptions of this content.METHODS: Maximum difference scaling (MaxDiff) methodology was used to develop a survey for assessing patients' understanding of 19 clinical terms and perceived importance of 9 endpoint surrogate phrases used in clinical trials and consent forms. The survey was administered electronically to individuals with metastatic breast cancer affiliated with the Metastatic Breast Cancer Alliance. Analyses were performed using Bayesian P values with statistical software.RESULTS: Among 503 respondents, 77% had a college degree, 70% were diagnosed with metastatic disease ≥2years before survey completion, and 77% had received ≥2 lines of systemic therapy. Less than 35% of respondents reported understanding "fairly well" the terms symptomatic progression, duration of disease control, time to treatment cessation, and endpoints. Income level and time since onset of metastatic disease correlated with comprehension. Patients who had received ≥6 lines of therapy perceived that time until serious side effects (P<.001) and time on therapy (P<.001) were more important compared with those who had received only 1 line of therapy. Positively phrased parameters were associated with increased perceived importance.CONCLUSIONS: Even among educated, heavily pretreated patients, many commonly used clinical research terms are poorly understood. Comprehension and the perceived importance of trial endpoints vary over the course of disease. These observations may inform the design, discussion, and reporting of clinical trials.
View details for DOI 10.1002/cncr.32730
View details for PubMedID 31967687
-
Novel Aza-podophyllotoxin derivative induces oxidative phosphorylation and cell death via AMPK activation in triple-negative breast cancer.
British journal of cancer
2020
Abstract
To circumvent Warburg effect, several clinical trials for different cancers are utilising a combinatorial approach using metabolic reprogramming and chemotherapeutic agents including metformin. The majority of these metabolic interventions work via indirectly activating AMP-activated protein kinase (AMPK) to alter cellular metabolism in favour of oxidative phosphorylation over aerobic glycolysis. The effect of these drugs is dependent on glycaemic and insulin conditions. Therefore, development of small molecules, which can activate AMPK, irrespective of the energy state, may be a better approach for triple-negative breast cancer (TNBC) treatment.Therapeutic effect of SU212 on TNBC cells was examined using in vitro and in vivo models.We developed and characterised the efficacy of novel AMPK activator (SU212) that selectively induces oxidative phosphorylation and decreases glycolysis in TNBC cells, while not affecting these pathways in normal cells. SU212 accomplished this metabolic reprogramming by activating AMPK independent of energy stress and irrespective of the glycaemic/insulin state. This leads to mitotic phase arrest and apoptosis in TNBC cells. In vivo, SU212 inhibits tumour growth, cancer progression and metastasis.SU212 directly activates AMPK in TNBC cells, but does not hamper glucose metabolism in normal cells. Our study provides compelling preclinical data for further development of SU212 for the treatment of TNBC.
View details for DOI 10.1038/s41416-020-01137-4
View details for PubMedID 33139797
-
Patient-Reported Cognitive Impairment Among Women With Early Breast Cancer Randomly Assigned to Endocrine Therapy Alone Versus Chemoendocrine Therapy: Results From TAILORx.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2020: JCO1901866
Abstract
Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI.Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors.FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant.Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.
View details for DOI 10.1200/JCO.19.01866
View details for PubMedID 32271671
-
Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer in the randomized TAILORx trial.
Journal of the National Cancer Institute
2020
Abstract
Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene Recurrence Score (RS), treatment delivered and clinical outcomes by race and ethnicity among women who participated in TAILORx.The association between clinical outcomes and race (White, Black, Asian, other/unknown) and ethnicity (Hispanic vs. non-Hispanic) was examined using proportional hazards models. All P values are two-sided.Of 9719 eligible women with hormone-receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7,1%) Blacks, 405 (4.2%) Asians, and 432 (4,4%) with other/unknown race. Regarding ethnicity, 889 (9,1%) were Hispanic. There were no substantial differences in RS or ESR1, PgR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41), and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25.Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in TAILORx. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.
View details for DOI 10.1093/jnci/djaa148
View details for PubMedID 32986828
-
Analysis of Overall Survival Benefit of Abemaciclib Plus Fulvestrant in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer-Reply.
JAMA oncology
2020
View details for DOI 10.1001/jamaoncol.2020.1518
View details for PubMedID 32463426
-
Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations
JNCI CANCER SPECTRUM
2019; 3 (4)
View details for DOI 10.1093/jncics/pkz050
View details for Web of Science ID 000503271700003
-
Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions.
JNCI cancer spectrum
2019; 3 (4): pkz049
Abstract
Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.
View details for DOI 10.1093/jncics/pkz049
View details for PubMedID 32337478
View details for PubMedCentralID PMC7050024
-
Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations.
JNCI cancer spectrum
2019; 3 (4): pkz050
Abstract
Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor-positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor-positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.
View details for DOI 10.1093/jncics/pkz050
View details for PubMedID 32337479
View details for PubMedCentralID PMC7049988
-
Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions
JNCI CANCER SPECTRUM
2019; 3 (4)
View details for DOI 10.1093/jncics/pkz049
View details for Web of Science ID 000503271700002
-
THE ROLE OF BIG DATA AND REAL WORLD DATA
CHURCHILL LIVINGSTONE. 2019: S22
View details for DOI 10.1016/S0960-9776(19)30615-0
View details for Web of Science ID 000502083600005
-
Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy.
The oncologist
2019
Abstract
BACKGROUND: In the phase III MONARCH 2 study (NCT02107703), abemaciclib plus fulvestrant significantly improved progression-free survival (PFS) versus placebo plus fulvestrant in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). This study assessed patient-reported pain, global health-related quality of life (HRQoL), functioning, and symptoms.MATERIALS AND METHODS: Abemaciclib or placebo (150 p.o. mg twice daily) plus fulvestrant (500 mg, per label) were randomly assigned (2:1). The modified Brief Pain Inventory, Short Form (mBPI-sf); European Organization for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30); and Breast Cancer Questionnaire (QLQ-BR23) assessed outcomes. Data were collected at baseline, cycle 2, every two cycles 3-13, thereafter at every three cycles, and 30days postdiscontinuation. Longitudinal mixed regression and Cox proportional hazards models assessed postbaseline change and time to sustained deterioration (TTSD) by study arm.RESULTS: On-treatment HRQoL scores were consistently maintained from baseline and similar between arms. Patients in the abemaciclib arm (n =446) experienced a 4.9-month delay in pain deterioration (mBPI-sf), compared with the control arm (n =223), and significantly greater TTSD on the mBPI-sf and analgesic use (hazard ratio, 0.76; 95% CI, 0.59-0.98) and QLQ-C30 pain item (hazard ratio, 0.62; 95% CI, 0.48-0.79). TTSD for functioning and most symptoms significantly favored the abemaciclib arm, including fatigue, nausea and vomiting, and cognitive and social functioning. Only diarrhea significantly favored the control arm (hazard ratio, 1.60; 95% CI, 1.20-2.10).CONCLUSION: HRQoL was maintained on abemaciclib plus fulvestrant. Alongside superior PFS and manageable safety profile, results support treatment with abemaciclib plus fulvestrant in a population of patients with endocrine-resistant HR+, HER2-negative ABC.IMPLICATIONS FOR PRACTICE: In MONARCH 2, abemaciclib plus fulvestrant demonstrated superior efficacy and a manageable safety profile for patients with in hormone receptor-positive (HR+), HER2-negative (-) advanced breast cancer (ABC). Impact on health-related quality of life (HRQoL) is important to consider, given the palliative nature of ABC treatment. In this study, abemaciclib plus fulvestrant, compared with placebo plus fulvestrant, significantly delayed sustained deterioration of pain and other patient-reported symptoms (including fatigue, nausea, vomiting), and social and cognitive functioning. Combined with demonstrated clinical benefit and tolerability, the stabilization of patient-reported symptoms and HRQoL further supports abemaciclib plus fulvestrant as a desirable treatment option in endocrine resistant, HR+, HER2- ABC.
View details for DOI 10.1634/theoncologist.2019-0551
View details for PubMedID 31649135
-
Susan G. Komen Big Data for Breast Cancer Initiative: How Patient Advocacy Organizations Can Facilitate Using Big Data to Improve Patient Outcomes
JCO PRECISION ONCOLOGY
2019; 3
View details for DOI 10.1200/PO.19.00184
View details for Web of Science ID 000488829500001
-
Susan G. Komen Big Data for Breast Cancer Initiative: How Patient Advocacy Organizations Can Facilitate Using Big Data to Improve Patient Outcomes.
JCO precision oncology
2019; 3
Abstract
Integrating different types of data, including electronic health records, imaging data, administrative and claims databases, large data repositories, the Internet of Things, genomics, and other omics data, is both a challenge and an opportunity that must be tackled head on. We explore some of the challenges and opportunities in optimizing data integration to accelerate breast cancer discovery and improve patient outcomes. Susan G. Komen convened three meetings (2015, 2017, and 2018) with various stakeholders to discuss challenges, opportunities, and next steps to enhance the use of big data in the field of breast cancer. Meeting participants agreed that big data approaches can enhance the identification of better therapies, improve outcomes, reduce disparities, and optimize precision medicine. One challenge is that databases must be shared, linked with each other, standardized, and interoperable. Patients want to be active participants in research and their own care, and to control how their data are used. Many patients have privacy concerns and do not understand how sharing their data can help to effectively drive discovery. Public education is essential, and breast cancer researchers who are skilled in using and analyzing big data are needed. Patient advocacy groups can play multiple roles to help maximize and leverage big data to better serve patients. Komen is committed to educating patients on big data issues, encouraging data sharing by all stakeholders, assisting in training the next generation of data science breast cancer researchers, and funding research projects that will use real-life data in real time to revolutionize the way breast cancer is understood and treated.
View details for DOI 10.1200/PO.19.00184
View details for PubMedID 32923852
View details for PubMedCentralID PMC7446366
-
Investigating circulating tumor cells and distant metastases in patient-derived orthotopic xenograft models of triple-negative breast cancer.
Breast cancer research : BCR
2019; 21 (1): 98
Abstract
BACKGROUND: Circulating tumor cells (CTCs) represent a temporal "snapshot" of a patient's cancer and changes that occur during disease evolution. There is an extensive literature studying CTCs in breast cancer patients, and particularly in those with metastatic disease. In parallel, there is an increasing use of patient-derived models in preclinical investigations of human cancers. Yet studies are still limited demonstrating CTC shedding and metastasis formation in patient-derived models of breast cancer.METHODS: We used seven patient-derived orthotopic xenograft (PDOX) models generated from triple-negative breast cancer (TNBC) patients to study CTCs and distant metastases. Tumor fragments from PDOX tissue from each of the seven models were implanted into 57 NOD scid gamma (NSG) mice, and tumor growth and volume were monitored. Human CTC capture from mouse blood was first optimized on the marker-agnostic Vortex CTC isolation platform, and whole blood was processed from 37 PDOX tumor-bearing mice.RESULTS: Staining and imaging revealed the presence of CTCs in 32/37 (86%). The total number of CTCs varied between different PDOX tumor models and between individual mice bearing the same PDOX tumors. CTCs were heterogeneous and showed cytokeratin (CK) positive, vimentin (VIM) positive, and mixed CK/VIM phenotypes. Metastases were detected in the lung (20/57, 35%), liver (7/57, 12%), and brain (1/57, less than 2%). The seven different PDOX tumor models displayed varying degrees of metastatic potential, including one TNBC PDOX tumor model that failed to generate any detectable metastases (0/8 mice) despite having CTCs present in the blood of 5/5 tested, suggesting that CTCs from this particular PDOX tumor model may typify metastatic inefficiency.CONCLUSION: PDOX tumor models that shed CTCs and develop distant metastases represent an important tool for investigating TNBC.
View details for DOI 10.1186/s13058-019-1182-4
View details for PubMedID 31462307
-
Clinical significance of PIK3CA and ESR1 mutations in ctDNA and FFPE samples from the MONARCH 2 study of abemaciclib plus fulvestrant
AMER ASSOC CANCER RESEARCH. 2019
View details for DOI 10.1158/1538-7445.AM2019-4458
View details for Web of Science ID 000488279404337
-
Radiomics features to identify distinct subtypes of triple-negative breast cancers.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.3069
View details for Web of Science ID 000487345805003
-
Impact of clinical risk category on prognosis and prediction of chemotherapy benefit in early breast cancer (EBC) by age and the 21-gene recurrence score (RS) in TAILORx.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.503
View details for Web of Science ID 000487345803496
-
Targeting CXCR4-induced desmoplasia to improve checkpoint inhibition in breast cancer
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2019; 116 (11): 4769–71
View details for DOI 10.1073/pnas.1900368116
View details for Web of Science ID 000460911500009
-
Patients and Physicians in the Era of Modern Cancer Care
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2019; 321 (9): 829–30
View details for DOI 10.1001/jama.2018.17334
View details for Web of Science ID 000460351600007
-
Targeting CXCR4-induced desmoplasia to improve checkpoint inhibition in breast cancer.
Proceedings of the National Academy of Sciences of the United States of America
2019
View details for PubMedID 30796186
-
Patients and Physicians in the Era of Modern Cancer Care.
JAMA
2019
View details for PubMedID 30768154
-
Gold Nanobipyramids as Second Near Infrared Optical Coherence Tomography Contrast Agents for in Vivo Multiplexing Studies.
Nano letters
2019
Abstract
Developing contrast-enhanced optical coherence tomography (OCT) techniques is important for specific imaging of tissue lesions, molecular imaging, cell-tracking, and highly sensitive microangiography and lymphangiography. Multiplexed OCT imaging in the second near-infrared (NIR-II) window is highly desirable since it allows simultaneous imaging and tracking of multiple biological events in high resolution with deeper tissue penetration in vivo. Here we demonstrate that gold nanobipyramids can function as OCT multiplexing contrast agents, allowing high-resolution imaging of two separate lymphatic flows occurring simultaneously from different drainage basins into the same lymph node in a live mouse. Contrast-enhanced multiplexed lymphangiography of a melanoma tumor in vivo shows that the peritumoral lymph flow upstream of the tumor is unidirectional, and tumor is accessible to such flow. Whereas the lymphatic drainage coming out from the tumor is multidirectional. We also demonstrate real-time tracking of the contrast agents draining from a melanoma tumor specifically to the sentinel lymph node of the tumor and the three-dimensional distribution of the contrast agents in the lymph node.
View details for DOI 10.1021/acs.nanolett.9b03344
View details for PubMedID 31585502
-
Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy: A Secondary Analysis of the TAILORx Randomized Clinical Trial.
JAMA oncology
2019
Abstract
A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit.To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone.In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on on May 12, 2019.The adjuvant chemotherapy regimen was selected by the treating physician.Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]).Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%).The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population.ClinicalTrials.gov identifier NCT00310180.
View details for DOI 10.1001/jamaoncol.2019.4794
View details for PubMedID 31566680
-
The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial.
JAMA oncology
2019
Abstract
Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated.To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET.MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019.Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary).The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02.Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib.Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy.ClinicalTrials.gov Identifier: NCT02107703.
View details for DOI 10.1001/jamaoncol.2019.4782
View details for PubMedID 31563959
-
Real-Time Detection of Circulating Tumor Cells in Living Animals Using Functionalized Large Gold Nanorods.
Nano letters
2019; 19 (4): 2334–42
Abstract
Optical coherence tomography (OCT) can be utilized with significant speckle reduction techniques and highly scattering contrast agents for non-invasive, contrast-enhanced imaging of living tissues at the cellular scale. The advantages of reduced speckle noise and improved targeted contrast can be harnessed to track objects as small as 2 μm in vivo, which enables applications for cell tracking and quantification in living subjects. Here we demonstrate the use of large gold nanorods as contrast agents for detecting individual micron-sized polystyrene beads and single myeloma cells in blood circulation using speckle-modulating OCT. This report marks the first time that OCT has been used to detect individual cells within blood in vivo. This technical capability unlocks exciting opportunities for dynamic detection and quantification of tumor cells circulating in living subjects.
View details for PubMedID 30895796
-
Personalized Decision Making in Early Stage Breast Cancer: Applying Clinical Prediction Models for Anthracycline Cardiotoxicity and Breast Cancer Mortality Demonstrates Substantial Heterogeneity of Benefit-Harm Trade-off.
Clinical breast cancer
2019
Abstract
Anthracycline agents can cause cardiotoxicity. We used multivariable risk prediction models to identify a subset of patients with breast cancer at high risk of cardiotoxicity, for whom the harms of anthracycline chemotherapy may balance or exceed the benefits.A clinical prediction model for anthracycline cardiotoxicity was created in 967 patients with human epidermal growth factor receptor-negative breast cancer treated with doxorubicin in the ECOG-ACRIN study E5103. Cardiotoxicity was defined as left ventricular ejection fraction (LVEF) decline of ≥ 10% to < 50% and/or a centrally adjudicated clinical heart failure diagnosis. Patient-specific incremental absolute benefit of anthracyclines (compared with non-anthracycline taxane chemotherapy) was estimated using the PREDICT model to assess breast cancer mortality risk.Of the 967 women who initiated therapy, 51 (5.3%) developed cardiotoxicity (12 with clinical heart failure). In a multivariate model, increasing age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.08), higher body mass index (OR, 1.06; 95% CI, 1.02-1.10), and lower baseline LVEF (OR, 0.93; 95% CI, 0.89-0.98) at baseline were significantly associated with cardiotoxicity. The concordance statistic of the risk model was 0.70 (95% CI, 0.63-0.77). In patients with low anticipated treatment benefit (n = 176) from the addition of anthracycline (< 2% absolute risk difference of breast cancer mortality at 10 years), 16 (9%) of 176 had a > 10% risk of cardiotoxicity and 61 (35%) of 176 had a 5% to 10% risk of cardiotoxicity at 1 year.Older age, higher body mass index, and lower baseline LVEF were associated with increased risk of cardiotoxicity. We identified a subgroup with low predicted absolute benefit of anthracyclines but with high predicted risk of cardiotoxicity. Additional studies are needed incorporating long-term cardiac outcomes and cardiotoxicity model external validation prior to implementation in routine clinical practice.
View details for DOI 10.1016/j.clbc.2019.04.012
View details for PubMedID 31175052
-
Using natural language processing to construct a metastatic breast cancer cohort from linked cancer registry and electronic medical records data.
JAMIA open
2019; 2 (4): 528–37
Abstract
Most population-based cancer databases lack information on metastatic recurrence. Electronic medical records (EMR) and cancer registries contain complementary information on cancer diagnosis, treatment and outcome, yet are rarely used synergistically. To construct a cohort of metastatic breast cancer (MBC) patients, we applied natural language processing techniques within a semisupervised machine learning framework to linked EMR-California Cancer Registry (CCR) data.We studied all female patients treated at Stanford Health Care with an incident breast cancer diagnosis from 2000 to 2014. Our database consisted of structured fields and unstructured free-text clinical notes from EMR, linked to CCR, a component of the Surveillance, Epidemiology and End Results Program (SEER). We identified de novo MBC patients from CCR and extracted information on distant recurrences from patient notes in EMR. Furthermore, we trained a regularized logistic regression model for recurrent MBC classification and evaluated its performance on a gold standard set of 146 patients.There were 11 459 breast cancer patients in total and the median follow-up time was 96.3 months. We identified 1886 MBC patients, 512 (27.1%) of whom were de novo MBC patients and 1374 (72.9%) were recurrent MBC patients. Our final MBC classifier achieved an area under the receiver operating characteristic curve (AUC) of 0.917, with sensitivity 0.861, specificity 0.878, and accuracy 0.870.To enable population-based research on MBC, we developed a framework for retrospective case detection combining EMR and CCR data. Our classifier achieved good AUC, sensitivity, and specificity without expert-labeled examples.
View details for DOI 10.1093/jamiaopen/ooz040
View details for PubMedID 32025650
View details for PubMedCentralID PMC6994019
-
Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy
NPJ BREAST CANCER
2018; 4
View details for DOI 10.1038/s41523-018-0094-2
View details for Web of Science ID 000462244300001
-
Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor-Positive Breast Cancer A Secondary Analysis of a Randomized Clinical Trial
JAMA ONCOLOGY
2018; 4 (12): 1700–1706
Abstract
Late recurrence 5 or more years after diagnosis accounts for at least one-half of all cases of recurrent hormone receptor-positive breast cancer.To determine whether the presence of circulating tumor cells (CTCs) in a peripheral blood sample obtained approximately 5 years after diagnosis was associated with late clinical recurrence of operable human epidermal growth factor receptor 2-negative breast cancer.This per-protocol secondary analysis of the Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer enrolled patients from 2007 to 2011 who were without clinical evidence of recurrence between 4.5 and 7.5 years after primary surgical treatment of human epidermal growth factor receptor 2-negative stage II-III breast cancer followed by adjuvant systemic therapy. Patients were enrolled in a subprotocol for secondary analysis from February 25, 2013, to July 29, 2016, after signing consent for the subprotocol. The analysis was performed in April 2018.A blood sample was obtained for identification and enumeration of CTCs.The association between a positive CTC assay result (at least 1 CTC per 7.5 mL of blood) and clinical recurrence.Among 547 women included in this analysis, the results of the CTC assay were positive for 18 of 353 with hormone receptor-positive disease (5.1% [95% CI, 3.0%-7.9%]); 23 of 353 patients (6.5% [95% CI, 4.2%-9.6%]) had a clinical recurrence. The recurrence rates per person-year of follow-up in the CTC-positive and CTC-negative groups were 21.4% (7 recurrences per 32.7 person-years) and 2.0% (16 recurrences per 796.3 person-years), respectively. In multivariate models including clinical covariates, a positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (hazard ratio point estimate, 13.1; 95% CI, 4.7-36.3). Seven of 23 patients (30.4% [95% CI, 13.2%-52.9%]) with recurrence had a positive CTC assay result at a median of 2.8 years (range, 0.1-2.8 years) before clinical recurrence. The CTC assay result was also positive for 8 of 193 patients (4.1% [95% CI, 1.8%-8.0%]) with hormone receptor-negative disease, although only 1 patient (0.5% [95% CI, 0%-2.9%]) experienced disease recurrence (this patient was CTC negative).A single positive CTC assay result 5 years after diagnosis of hormone receptor-positive breast cancer provided independent prognostic information for late clinical recurrence, which provides proof of concept that liquid-based biomarkers may be used to risk stratify for late recurrence and guide therapy.ClinicalTrials.gov identifier: NCT00433511.
View details for DOI 10.1001/jamaoncol.2018.2574
View details for Web of Science ID 000453212800014
View details for PubMedID 30054636
-
Change in Survival in Metastatic Breast Cancer with Treatment Advances: Meta-Analysis and Systematic Review.
JNCI cancer spectrum
2018; 2 (4): pky062
Abstract
Metastatic breast cancer (MBC) treatment has changed substantially over time, but we do not know whether survival post-metastasis has improved at the population level.We searched for studies of MBC patients that reported survival after metastasis in at least two time periods between 1970 and the present. We used meta-regression models to test for survival improvement over time in four disease groups: recurrent, recurrent estrogen (ER)-positive, recurrent ER-negative, and de novo stage IV. We performed sensitivity analyses based on bias in some studies that could lead earlier cohorts to include more aggressive cancers.There were 15 studies of recurrent MBC (N = 18 678 patients; 3073 ER-positive and 1239 ER-negative); meta-regression showed no survival improvement among patients recurring between 1980 and 1990, but median survival increased from 21 (95% confidence interval [CI] = 18 to 25) months to 38 (95% CI = 31 to 47) months from 1990 to 2010. For ER-positive MBC patients, median survival increased during 1990-2010 from 32 (95% CI = 23 to 43) to 57 (95% CI = 37 to 87) months, and for ER-negative MBC patients from 14 (95% CI = 11 to 19) to 33 (95% CI = 21 to 51) months. Among eight studies (N = 35 831) of de novo stage IV MBC, median survival increased during 1990-2010 from 20 (95% CI = 16 to 24) to 31 (95% CI = 24 to 39) months. Results did not change in sensitivity analyses.By bridging studies over time, we demonstrated improvements in survival for recurrent and de novo stage IV MBC overall and across ER-defined subtypes since 1990. These results can inform patient-doctor discussions about MBC prognosis and therapy.
View details for DOI 10.1093/jncics/pky062
View details for PubMedID 30627694
View details for PubMedCentralID PMC6305243
-
Tumor Molecular Profiling Aids in Determining Tissue of Origin and Therapy for Metastatic Adenocarcinoma in a Patient With Multiple Primary Malignancies
JCO PRECISION ONCOLOGY
2018; 2
View details for DOI 10.1200/PO.18.00177
View details for Web of Science ID 000462187500001
-
Effects of Celecoxib and Low-dose Aspirin on Outcomes in Adjuvant Aromatase Inhibitor-Treated Patients: CCTG MA.27
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
2018; 110 (9): 1003–8
Abstract
Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence.In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor-positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease-free survival (DDFS); and overall survival (OS). All statistical tests were two-sided.Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years' follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non-aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01).Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased "all-cause" mortality, presumably because of higher preexisting cardiovascular risks.
View details for PubMedID 29554282
-
Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103)
JOURNAL OF CLINICAL ONCOLOGY
2018; 36 (25): 2621-+
View details for DOI 10.1200/JCO.2018.79.2028
View details for Web of Science ID 000445669200008
-
Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103).
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2018: JCO2018792028
Abstract
Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.
View details for PubMedID 30040523
-
The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3
AMER ASSOC CANCER RESEARCH. 2018
View details for DOI 10.1158/1538-7445.AM2018-CT099
View details for Web of Science ID 000468818900091
-
TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for Web of Science ID 000443284700002
-
Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer
CLINICAL CANCER RESEARCH
2018; 24 (12): 2851–58
View details for DOI 10.1158/1078-0432.CCR-17-1323
View details for Web of Science ID 000435462700016
-
Local Control of Distant Disease: Yes, but Where to Next?
Journal of oncology practice
2018; 14 (6): 357–58
View details for PubMedID 29894663
-
Local Control of Distant Disease: Yes, but Where to Next?
JOURNAL OF ONCOLOGY PRACTICE
2018; 14 (6): 357-+
View details for DOI 10.1200/JOP.18.00247
View details for Web of Science ID 000437899100013
-
Patient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03)
BREAST CANCER RESEARCH AND TREATMENT
2018; 169 (3): 537–48
Abstract
Aromatase inhibitors are the most commonly prescribed adjuvant endocrine therapy for hormone-dependent early breast cancer in postmenopausal women. Among Canadian Cancer Trials Group MA.27 participants, anastrozole and exemestane had comparable 5-year event-free survival. This companion study examined differences in patient-reported treatment-related symptoms (TRS) and health-related quality of life (HRQL) among postmenopausal women randomized to anastrozole or exemestane.MA.27 participants (N = 686, of 7576) randomized to 5 years of anastrozole (1 mg/day, n = 371, Arm A) or exemestane (25 mg/day, n = 315, Arm E) completed the 56-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire to assess TRS and HRQL. The FACT-ES was completed at baseline, 3, 6, 12, and 24 months.No significant differences in FACT-ES median scores measuring TRS and HRQL were observed between treatment arms at any time point. Change in TRS from baseline was statistically significant at 3, 6, 12, and 24 months. HRQL was stable over time in both arms. Greater TRS burden was associated with poorer HRQL (coefficient = 0.57, p < 0.001). Twenty percent of patients discontinued AI therapy by month 24 and 32% discontinued AIs at 4 years. In both arms, patients reporting more side effect bother prior to initiating study treatment had a higher risk of discontinuing treatment before completing protocol therapy (hazard ratio [HR] 1.29, 95% CI 1.08-1.55, p = 0.01).TRS and HRQL were comparable between anastrozole and exemestane. TRS negatively affect HRQL. Women who report being bothered by treatment side effects prior to initiating an AI are at increased risk for early treatment discontinuation.
View details for PubMedID 29455298
-
Urgent hypertension as a biomarker for bevacizumab in the curative setting.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.548
View details for Web of Science ID 000442916000057
-
Impact of abemaciclib on the time to subsequent chemotherapy and the time to second disease progression across the MONARCH 2 and 3 studies
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.1048
View details for Web of Science ID 000442916001070
-
Symptom burden and employment status in breast cancer (BC) survivors.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.10073
View details for Web of Science ID 000442916003438
-
Health-related quality of life (HRQoL) in MONARCH 2: Abemaciclib plus fulvestrant in women with HR+, HER2-advanced breast cancer (ABC) who progressed on endocrine therapy
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.1049
View details for Web of Science ID 000442916001071
-
The association of early toxicity and outcomes for patients treated with abemaciclib
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.1053
View details for Web of Science ID 000442916001075
-
Abemaciclib for pre/perimenopausal women with HR+, HER2-advanced breast cancer
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.1002
View details for Web of Science ID 000442916001026
-
Altered expression of telomere-associated genes in leukocytes among BRCA1 and BRCA2 carriers
MOLECULAR CARCINOGENESIS
2018; 57 (4): 567–75
Abstract
Telomere dysfunction resulting from telomere shortening and deregulation of shelterin components has been linked to the pathogenesis of age-related disorders, including cancer. Recent evidence suggests that BRCA1/2 (BRCA1 and BRCA2) tumor suppressor gene products play an important role in telomere maintenance. Although telomere shortening has been reported in BRCA1/2 carriers, the direct effects of BRCA1/2 haploinsufficiency on telomere maintenance and predisposition to cancer development are not completely understood. In this study, we assessed the telomere-associated and telomere-proximal gene expression profiles in peripheral blood leukocytes from patients with a BRCA1 or BRCA2 mutation, compared to samples from sporadic and familial breast cancer individuals. We found that 25 genes, including TINF2 gene (a negative regulator of telomere length), were significantly differentially expressed in BRCA1 carriers. Leukocyte telomere length analysis revealed that BRCA1/2 carriers had relatively shorter telomeres than healthy controls. Further, affected BRCA1/2 carriers were well differentiated from unaffected BRCA1/2 carriers by the expression of telomere-proximal genes. Our results link BRCA1/2 haploinsufficiency to changes in telomere length, telomere-associated as well as telomere-proximal gene expression. Thus, this work supports the effect of BRCA1/2 haploinsufficiency in the biology underlying telomere dysfunction in cancer development. Future studies evaluating these findings will require a large study population.
View details for PubMedID 29240257
View details for PubMedCentralID PMC5832588
-
Molecular characterization and mortality from breast cancer in men
AMER ASSOC CANCER RESEARCH. 2018
View details for Web of Science ID 000425489402296
-
Circulating tumor cells (CTCs) five years after diagnosis are prognostic for late recurrence in operable stage II-III breast cancer
AMER ASSOC CANCER RESEARCH. 2018
View details for Web of Science ID 000425489400039
-
Efficacy and safety of abemaciclib in patients with liver metastases in the MONARCH 1, 2, and 3 studies
AMER ASSOC CANCER RESEARCH. 2018
View details for Web of Science ID 000425489402037
-
The benefit of abemaciclib in prognostic subgroups: An exploratory analysis of combined data from the MONARCH 2 and 3 studies
AMER ASSOC CANCER RESEARCH. 2018
View details for Web of Science ID 000425489400038
-
Molecular Characterization and Mortality From Breast Cancer in Men.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2018: JCO2017768861
Abstract
Purpose Limited data exist on the molecular biology, treatment, and outcomes of breast cancer in men, and much of our understanding in this area remains largely an extrapolation from data in women with breast cancer. Materials and Methods We studied men and women with hormone receptor-positive breast cancer and the 21-gene Breast Recurrence Score (RS) results. Differences in clinical characteristics and gene expression were determined, and distribution of RS results was correlated with 5-year breast cancer-specific survival (BCSS) and overall survival. Results There were 3,806 men and 571,115 women. Men were older than women (mean age, 64.2 v 59.1 years; P < .001). RS < 18 predominated in both genders, but RS ≥ 31 was more frequent in men (12.4% v 7.4%; P < .001), as were very low scores (RS < 11; 33.8% v 22.1%; P < .001). Mean gene expression was higher in men for the estrogen receptor (ER), proliferation, and invasion groups. ER was lowest and progesterone receptor was highest in women younger than 50 years of age, with a progressive increase in ER with age. Men younger than 50 years of age had slightly lower ER and progesterone receptor compared with older men. Survival data were available from SEER for 322 men and 55,842 women. Five-year BCSS was 99.0% (95% CI, 99.3% to 99.9%) and 95.9% (95% CI, 87.6% to 98.7%) for men with RS < 18 and RS 18-30, respectively, and for women, it was 99.5% (95% CI, 99.4% to 99.6%) and 98.6% (95% CI, 98.4% to 98.8%), respectively. RS ≥ 31 was associated with an 81.0% 5-year BCSS in men (95% CI, 53.3% to 93.2%) and 94.9% 5-year BCSS (95% CI, 93.9% to 95.7%) in women. Five-year BCSS and overall survival were lower in men than in women. Conclusion This study reveals some distinctive biologic features of breast cancer in men and an important prognostic role for RS testing in both men and women.
View details for PubMedID 29584547
-
Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.
NPJ breast cancer
2018; 4: 41
Abstract
CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI≥36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.
View details for PubMedID 30588487
-
Change in survival in metastatic breast cancer with treatment advances: meta-analysis and systematic review
JNCI Cancer Spectrum
2018; 2 (4)
View details for DOI 10.1093/jncics/pky062
-
Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research
2018
Abstract
Tumor-infiltrating lymphocytes (TILs) in pre-treatment biopsies are associated with improved survival in triple-negative breast cancer (TNBC). We investigated whether higher peripheral lymphocyte counts are associated with lower breast cancer-specific mortality (BCM) and overall mortality (OM) in TNBC.Data on treatments and diagnostic tests from electronic medical records of two healthcare systems were linked with demographic, clinical, pathologic, and mortality data from the California Cancer Registry. Multivariable regression models adjusted for age, race/ethnicity, socioeconomic status, cancer stage, grade, neoadjuvant/adjuvant chemotherapy use, radiotherapy use, and germline BRCA1/2 mutations were used to evaluate associations between absolute lymphocyte count (ALC), BCM and OM. For a subgroup with TILs data available, we explored the relationship between TILs and peripheral lymphocyte counts.1,463 Stage I-III TNBC patients were diagnosed from 2000-2014; 1113 (76%) received neoadjuvant/adjuvant chemotherapy within one year of diagnosis. Of 759 patients with available ALC data, 481 (63.4%) were ever lymphopenic (minimum ALC <1.0 K/μL). On multivariable analysis, higher minimum ALC, but not absolute neutrophil count, predicted lower OM (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.16-0.35) and BCM (HR: 0.19, CI: 0.11-0.34). Five-year probability of BCM was 15% for patients who were ever lymphopenic versus 4% for those who were not. An exploratory analysis (N=70) showed a significant association between TILs and higher peripheral lymphocyte counts during neoadjuvant chemotherapy.Higher peripheral lymphocyte counts predicted lower mortality from early-stage, potentially curable TNBC, suggesting that immune function may enhance the effectiveness of early TNBC treatment.
View details for PubMedID 29581131
-
PRECISION/PERSONALIZED MEDICINE: HOPES AND HYPES
CHURCHILL LIVINGSTONE. 2017: S26
View details for Web of Science ID 000414258900022
-
Does biomarker information impact breast cancer patients' preferences and physician recommendation for adjuvant chemotherapy?
BREAST CANCER RESEARCH AND TREATMENT
2017; 165 (3): 545–53
Abstract
This study aimed to examine how biomarker information would impact patients' preferences and physicians' recommendations for adjuvant breast cancer therapy.At the 18-month follow-up, participants in a large, double-blind randomized controlled trial of adjuvant chemotherapy with bevacizumab or placebo (E5103) were surveyed about their preferred treatment (either chemotherapy A alone or chemotherapy A+B) in two hypothetical scenarios: (1) without biomarker information; and (2) after learning that they tested positive for a "B-receptor" which modestly increased both the benefit and toxicity expected with chemotherapy A+B. We performed a cross-sectional analysis of the prospectively collected survey data and used the McNemar's test to examine changes in treatment preferences. A one-time survey of clinical investigators who enrolled patients on the trial evaluated physician recommendations in response to the same biomarker information.439 patients completed both scenarios on 18-month survey. Most participants preferred A+B in both scenario 1 and 2 (77 and 76% respectively). The increase in benefit and toxicity associated with the positive biomarker information in scenario 2 led 60/439 (14%) of patients to switch their treatment preference. The corresponding physician survey revealed that most physicians chose regimen A+B in scenario 1 (77%), and moreso after the biomarker information was available in scenario 2 (84%).Information about a positive biomarker indicating increased benefit and toxicity from additional chemotherapy did not change many participants' preferred treatment. The majority preferred the most effective course in both scenarios. Similarly, most investigators discounted increased toxicity and valued increased benefit. Parent Trial Registration: NCT00433511.
View details for PubMedID 28646344
View details for PubMedCentralID PMC5837858
-
A Phase I/II study of suberoylanilide hydroxamic acid (SAHA) in combination with trastuzumab (Herceptin) in patients with advanced metastatic and/or local chest wall recurrent HER2-amplified breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1104)
BREAST CANCER RESEARCH AND TREATMENT
2017; 165 (2): 375–82
Abstract
Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease.In Phase I, the SAHA dose was modified in cohorts of 3-6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated.The recommended dose was determined to be 200 mg twice a day on days 1-14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle (n = 6). The Phase II study (n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment.In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients.
View details for PubMedID 28623430
View details for PubMedCentralID PMC5682621
-
Survival Benefit Needed to Undergo Chemotherapy: Patient and Physician Preferences
CANCER
2017; 123 (15): 2821–28
Abstract
Published studies have suggested that most patients with early stage breast cancer are willing, for modest survival benefits, to receive 6 months of adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil, an older regimen that is used infrequently today. We examined preferences regarding the survival benefit needed to justify 6 months of a contemporary chemotherapy regimen.The Eastern Cooperative Oncology Group Protocol 5103 was a phase 3 trial that randomized breast cancer patients to receive standard adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo. Serial surveys to assess quality of life were administered to patients enrolled between January 1, 2010, and June 8, 2010. Survival benefit needed to justify 6 months of chemotherapy by patients was collected at the 18-month assessment. A parallel survey was sent to physicians who had enrolled patients in the study.Of 519 patients who had not withdrawn at a time point earlier than 18 months, 87.8% responded to this survey. A total of 175 physicians participated. We found considerable variation in patient preferences, particularly for modest survival benefits: for 2 months of benefit, 57% would consider 6 months of chemotherapy, whereas 96% of patients would consider 6 months of chemotherapy for 24 months. Race and education were associated with the choices. Physicians who responded were less likely to accept chemotherapy for modest benefit.Among patients who received contemporary adjuvant chemotherapy in a randomized controlled trial, we found substantial variation in preferences regarding benefits that justified undergoing chemotherapy. Differences between patients' and physicians' choices were also apparent. Eliciting preferences regarding risks and benefits of adjuvant chemotherapy is critical. Cancer 2017;123:2821-28. © 2017 American Cancer Society.
View details for DOI 10.1002/cncr.30671
View details for Web of Science ID 000405826400007
View details for PubMedID 28323331
View details for PubMedCentralID PMC5517352
-
MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy.
Journal of clinical oncology
2017: JCO2017737585-?
Abstract
Purpose MONARCH 2 ( ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC). Patients and Methods MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety. Results Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%). Conclusions Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET.
View details for DOI 10.1200/JCO.2017.73.7585
View details for PubMedID 28580882
-
MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/HER2-advanced breast cancer who progressed on endocrine therapy
AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.1000
View details for Web of Science ID 000411895701137
-
Osteoporosis therapy and outcomes for postmenopausal patients with hormone receptor-positive breast cancer: NCIC CTG MA.27.
Cancer
2017
Abstract
Breast cancer patients in the MA.27 trial had similar outcomes with steroidal aromatase inhibitor (AI) exemestane and nonsteroidal anastrozole. AIs increase the risk of osteoporosis. This study examined the effects of self-reported osteoporosis and osteoporosis therapy (OPT) on outcomes.The MA.27 phase 3 adjuvant trial enrolled 7576 postmenopausal women. The primary outcome was event-free survival (EFS), and the secondary outcome was distant disease-free survival (DDFS). Patients were permitted bisphosphonates to prevent or treat osteopenia/osteoporosis. In a multivariate, stratified Cox regression, factors were significant with a 2-sided Wald test P value ≤ .05.Osteoporosis was reported at the baseline by 654 of the 7576 women (8.6%) and in total by 1294 patients. Oral OPT was received at the baseline by 815 of the 7576 women (10.8%) and in total by 2711 patients (36%). With a median follow-up of 4.1 years, 693 EFS events (9.15%) and 321 DDFS events (4.2%) occurred. Osteoporosis was not associated with EFS or DDFS. Few EFS events occurred before the initiation of OPT, with no substantive evidence of a time-differing effect on outcomes (nonproportional hazards). OPT (yes vs no) was significantly associated with improved EFS (hazard ratio [HR] for yes vs no, 0.67; 95% confidence interval [CI], 0.57-0.80; P < .001) and DDFS (HR, 0.57; 95% CI, 0.44-0.73; P <. 001). Time-differing (time-dependent) OPT was not (EFS; P = .45). OPT did not alter the incidence of visceral-only metastasis (P = .31).Oral OPT, administered to postmenopausal breast cancer patients receiving adjuvant AI therapy, was associated with improved EFS and DDFS; the time of OPT initiation (a time-dependent effect) did not affect the outcome. OPT did not alter the risk of visceral metastasis. Cancer 2017;123:2444-51. © 2017 American Cancer Society.
View details for DOI 10.1002/cncr.30682
View details for PubMedID 28464211
-
Put Some PEPI in Your Step: Ki67's Long Road to Respectability.
Journal of clinical oncology
2017: JCO2016712182-?
View details for DOI 10.1200/JCO.2016.71.2182
View details for PubMedID 28221864
-
Research needs in breast cancer
ANNALS OF ONCOLOGY
2017; 28 (2): 208-217
View details for DOI 10.1093/annonc/mdw571
View details for Web of Science ID 000397278300007
-
Reply to L.B. Marks et al.
Journal of clinical oncology
2017: JCO2016713966-?
View details for PubMedID 28068171
-
Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure.
Clinical cancer research : an official journal of the American Association for Cancer Research
2017; 23 (1): 43-51
Abstract
Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline.We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE.When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10(-5), of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2).rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials. Clin Cancer Res; 23(1); 43-51. ©2016 AACR.
View details for DOI 10.1158/1078-0432.CCR-16-0908
View details for PubMedID 27993963
View details for PubMedCentralID PMC5215621
-
Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-E5103.
JCO precision oncology
2017; 2017
Abstract
Purpose: Racial disparity in breast cancer outcomes exists between African American and Caucasian women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for breast cancer patients in the context of a randomized, phase III adjuvant trial.Patients and Methods: This study compared outcomes between 386 patients of African ancestry (AA) and 2473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial; ECOG-ACRIN-E5103. The primary efficacy endpoint, invasive disease free survival (DFS) and clinically significant toxicities were compared including: anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension.Results: Overall, AAs had significantly inferior DFS (p=0.002; HR=1.5) compared with EAs. This was significant in the estrogen receptor-positive subgroup (p=0.03); with a similar, non-significant trend for those who had triple negative breast cancer (TNBC; p=0.12). AAs also had significantly more grade 3-4 TIPN (OR=2.9; p=2.4 *10-11) and grade 3-4 bevacizumab-induced hypertension (OR=1.6; p=0.02), with a trend for more CHF (OR=1.8; p=0.08). AAs had significantly more dose reductions for paclitaxel (p=6.6 *10-6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (p=0.03); whereas in EAs, dose reductions did not impact outcome (p=0.35).Conclusion: AAs had inferior DFS with more clinically important toxicities in ECOG-ACRIN-E5103. The altered risk to benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus centered on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions for paclitaxel, especially due to TIPN, are warranted for this population.
View details for PubMedID 29333527
-
Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-5103
JCO PRECISION ONCOLOGY
2017; 1
View details for Web of Science ID 000462058200050
-
Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update
ANNALS OF SURGICAL ONCOLOGY
2017; 24 (1): 38-51
Abstract
A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT).A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data.The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.
View details for DOI 10.1245/s10434-016-5558-8
View details for Web of Science ID 000391510400010
View details for PubMedID 27646018
View details for PubMedCentralID PMC5179596
-
Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update
JOURNAL OF CLINICAL ONCOLOGY
2016; 34 (36)
Abstract
Purpose A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). Methods A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. Recommendations The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.
View details for DOI 10.1200/JCO.2016.69.1188
View details for Web of Science ID 000391380500019
View details for PubMedID 27646947
-
Synergistic drug combinations from electronic health records and gene expression.
Journal of the American Medical Informatics Association
2016
Abstract
Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.We applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.From EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.This is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing.
View details for DOI 10.1093/jamia/ocw161
View details for PubMedID 27940607
-
Research needs in breast cancer.
Annals of oncology
2016
Abstract
New research questions emerge as medical needs continue to evolve and as we improve our understanding of cancer biology and treatment of malignancies. Although significant advances have been made in some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree and we continue to have many gaps in our knowledge. This article summarizes the 12 short and medium-term clinical research needs in breast cancer deemed as priorities in 2016 by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas: (i) de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes; (ii) explore optimal adjuvant treatment durations; (iii) develop better tools and strategies to identify patients with genetic predisposition; (iv) improve care in young patients with breast cancer; (v) develop tools to speed up drug development in biomarker-defined populations; (vi) identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-HER2 therapies; (vii) evaluate the efficacy of local-regional treatments for metastatic disease; (viii) better define the optimal sequence of treatments in the metastatic setting; (ix) evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity); (x) better understand the biology and identify new targets in triple-negative breast cancer; (xi) better understand immune surveillance in breast cancer and further develop immunotherapies; and (xii) increase survivorship research efforts including supportive care and quality of life.
View details for DOI 10.1093/annonc/mdw571
View details for PubMedID 27831505
-
Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.
Practical radiation oncology
2016; 6 (6): e219-e234
Abstract
A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT).A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data.The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.
View details for DOI 10.1016/j.prro.2016.08.009
View details for PubMedID 27659727
-
Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African-Americans.
Oncotarget
2016
Abstract
Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity.Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN.Five genes had a p-value < 10-4 for grade 3-4 TIPN analysis and three genes had a p-value < 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10-6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease.Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.
View details for DOI 10.18632/oncotarget.12545
View details for PubMedID 27732968
-
Aberrant nocturnal cortisol and disease progression in women with breast cancer
BREAST CANCER RESEARCH AND TREATMENT
2016; 158 (1): 43-50
Abstract
While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p's > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p < 0.004, Wilcoxon Signed-Rank). This cortisol aberration was associated with cancer progression such that the larger the aberration, the shorter the disease-free interval (time from initial diagnosis to metastasis; r = -0.30, p = 0.004; linear regression). The same aberrant spike was present in a similar percent of women without ABC and associated with concomitant sleep disruption. A greater understanding of this sleep-related cortisol abnormality, possibly a vulnerability trait, is likely important in our understanding of individual variation in the progression of cancer.
View details for DOI 10.1007/s10549-016-3864-2
View details for Web of Science ID 000379494200005
View details for PubMedID 27314577
View details for PubMedCentralID PMC4938753
-
Use of Gene Expression Profiling and Chemotherapy in Early-Stage Breast Cancer: A Study of Linked Electronic Medical Records, Cancer Registry Data, and Genomic Data Across Two Health Care Systems.
Journal of oncology practice / American Society of Clinical Oncology
2016; 12 (6): e697-709
Abstract
The 21-gene recurrence score (RS) identifies patients with breast cancer who derive little benefit from chemotherapy; it may reduce unwarranted variability in the use of chemotherapy. We tested whether the use of RS seems to guide chemotherapy receipt across different cancer care settings.We developed a retrospective cohort of patients with breast cancer by using electronic medical record data from Stanford University (hereafter University) and Palo Alto Medical Foundation (hereafter Community) linked with demographic and staging data from the California Cancer Registry and RS results from the testing laboratory (Genomic Health Inc., Redwood City, CA). Multivariable analysis was performed to identify predictors of RS and chemotherapy use.In all, 10,125 patients with breast cancer were diagnosed in the University or Community systems from 2005 to 2011; 2,418 (23.9%) met RS guidelines criteria, of whom 15.6% received RS. RS was less often used for patients with involved lymph nodes, higher tumor grade, and age < 40 or ≥ 65 years. Among RS recipients, chemotherapy receipt was associated with a higher score (intermediate v low: odds ratio, 3.66; 95% CI, 1.94 to 6.91). A total of 293 patients (10.6%) received care in both health care systems (hereafter dual use); although receipt of RS was associated with dual use (v University: odds ratio, 1.73; 95% CI, 1.18 to 2.55), there was no difference in use of chemotherapy after RS by health care setting.Although there was greater use of RS for patients who sought care in more than one health care setting, use of chemotherapy followed RS guidance in University and Community health care systems. These results suggest that precision medicine may help optimize cancer treatment across health care settings.
View details for DOI 10.1200/JOP.2015.009803
View details for PubMedID 27221993
View details for PubMedCentralID PMC4957259
-
Integrated digital error suppression for noninvasive detection of circulating tumor DNA in NSCLC.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e20500
View details for Web of Science ID 000404711506257
-
A phase II prospective trial correlating progression-free survival (PFS) with CYP2D6 activity in patients with metastatic breast cancer treated with tamoxifen: ECOG-ACRIN E3108.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.546
View details for Web of Science ID 000404665400053
-
Genome wide association study for anthracycline-induced congestive heart failure.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.1017
View details for Web of Science ID 000404665401139
-
Association of Charcot-Marie-Tooth gene, SBF2, with taxane-induced peripheral neuropathy in African Americans.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.1026
View details for Web of Science ID 000404665401147
-
Phase 1, open-label, dose-escalation and expansion study of ABT-165, a dual variable domain immunoglobulin (DVD-Ig) targeting both DLL4 and VEGF, in patients (pts) with advanced solid tumors.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.2507
View details for Web of Science ID 000404665403106
-
Higher peripheral lymphocyte count to predict survival in triple-negative breast cancer (TNBC).
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.1010
View details for Web of Science ID 000404665401132
-
Integrated digital error suppression for improved detection of circulating tumor DNA
NATURE BIOTECHNOLOGY
2016; 34 (5): 547-555
Abstract
High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.
View details for DOI 10.1038/nbt.3520
View details for PubMedID 27018799
-
Collective Wisdom: Lobular Carcinoma of the Breast.
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
2016: 18–21
View details for DOI 10.1200/EDBK_100002
View details for PubMedID 30372330
-
Adjuvant Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Detour on the Road to a Cure
JOURNAL OF CLINICAL ONCOLOGY
2016; 34 (10): 1021-+
View details for PubMedID 26700125
-
Classification of large circulating tumor cells isolated with ultra-high throughput microfluidic Vortex technology
ONCOTARGET
2016; 7 (11): 12748-12760
Abstract
Circulating tumor cells (CTCs) are emerging as rare but clinically significant non-invasive cellular biomarkers for cancer patient prognosis, treatment selection, and treatment monitoring. Current CTC isolation approaches, such as immunoaffinity, filtration, or size-based techniques, are often limited by throughput, purity, large output volumes, or inability to obtain viable cells for downstream analysis. For all technologies, traditional immunofluorescent staining alone has been employed to distinguish and confirm the presence of isolated CTCs among contaminating blood cells, although cells isolated by size may express vastly different phenotypes. Consequently, CTC definitions have been non-trivial, researcher-dependent, and evolving. Here we describe a complete set of objective criteria, leveraging well-established cytomorphological features of malignancy, by which we identify large CTCs. We apply the criteria to CTCs enriched from stage IV lung and breast cancer patient blood samples using the High Throughput Vortex Chip (Vortex HT), an improved microfluidic technology for the label-free, size-based enrichment and concentration of rare cells. We achieve improved capture efficiency (up to 83%), high speed of processing (8 mL/min of 10x diluted blood, or 800 μL/min of whole blood), and high purity (avg. background of 28.8±23.6 white blood cells per mL of whole blood). We show markedly improved performance of CTC capture (84% positive test rate) in comparison to previous Vortex designs and the current FDA-approved gold standard CellSearch assay. The results demonstrate the ability to quickly collect viable and pure populations of abnormal large circulating cells unbiased by molecular characteristics, which helps uncover further heterogeneity in these cells.
View details for PubMedID 26863573
-
Avoidant coping and self-efficacy mediate relationships between perceived social constraints and symptoms among long-term breast cancer survivors.
Psycho-oncology
2016
Abstract
Many breast cancer survivors feel constrained in discussing their cancer experience with others. Limited evidence suggests that social constraints (e.g., avoidance and criticism) from loved ones may negatively impact breast cancer survivors' global health, but research has yet to examine relationships between social constraints and common physical symptoms. Informed by social cognitive processing theory, this study examined whether perceived social constraints from partners and healthcare providers (HCPs) were associated with fatigue, sleep disturbance, and attentional functioning among long-term breast cancer survivors (N = 1052). In addition, avoidant coping and self-efficacy for symptom management were examined as potential mediators of these relationships.Long-term breast cancer survivors (mean years since diagnosis = 6) completed questionnaires assessing social constraints from partners and HCPs, avoidant coping, self-efficacy for symptom management, and symptoms (i.e., fatigue, sleep disturbance, and attentional functioning). Structural equation modeling was used to evaluate the hypothesized relationships among variables in two models: one focused on social constraints from partners and one focused on social constraints from HCPs.Both models demonstrated good fit. Consistent with theory and prior research, greater social constraints from both partners and HCPs were associated with greater symptom burden (i.e., greater fatigue and sleep disturbance, poorer attentional functioning). In addition, all relationships were mediated by avoidant coping and self-efficacy for symptom management.Findings are consistent with social cognitive processing theory and suggest that symptom management interventions may be enhanced by addressing the impact of social constraints from survivors' partners and HCPs on their coping and self-efficacy. Copyright © 2016 John Wiley & Sons, Ltd.
View details for DOI 10.1002/pon.4119
View details for PubMedID 26969374
View details for PubMedCentralID PMC5018239
-
Quality of life difficulties in partners of young breast cancer survivors.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/jco.2016.34.3_suppl.188
View details for Web of Science ID 000378109500178
-
Small-molecule binding sites to explore protein-protein interactions in the cancer proteome
MOLECULAR BIOSYSTEMS
2016; 12 (10): 3067-3087
Abstract
The Cancer Genome Atlas (TCGA) offers an unprecedented opportunity to identify small-molecule binding sites on proteins with overexpressed mRNA levels that correlate with poor survival. Here, we analyze RNA-seq and clinical data for 10 tumor types to identify genes that are both overexpressed and correlate with patient survival. Protein products of these genes were scanned for binding sites that possess shape and physicochemical properties that can accommodate small-molecule probes or therapeutic agents (druggable). These binding sites were classified as enzyme active sites (ENZ), protein-protein interaction sites (PPI), or other sites whose function is unknown (OTH). Interestingly, the overwhelming majority of binding sites were classified as OTH. We find that ENZ, PPI, and OTH binding sites often occurred on the same structure suggesting that many of these OTH cavities can be used for allosteric modulation of enzyme activity or protein-protein interactions with small molecules. We discovered several ENZ (PYCR1, QPRT, and HSPA6) and PPI (CASC5, ZBTB32, and CSAD) binding sites on proteins that have been seldom explored in cancer. We also found proteins that have been extensively studied in cancer that have not been previously explored with small molecules that harbor ENZ (PKMYT1, STEAP3, and NNMT) and PPI (HNF4A, MEF2B, and CBX2) binding sites. All binding sites were classified by the signaling pathways to which the protein that harbors them belongs using KEGG. In addition, binding sites were mapped onto structural protein-protein interaction networks to identify promising sites for drug discovery. Finally, we identify pockets that harbor missense mutations previously identified from analysis of TCGA data. The occurrence of mutations in these binding sites provides new opportunities to develop small-molecule probes to explore their function in cancer.
View details for DOI 10.1039/c6mb00231e
View details for Web of Science ID 000384405400012
View details for PubMedID 27452673
View details for PubMedCentralID PMC5030169
-
Curing Metastatic Breast Cancer.
Journal of oncology practice / American Society of Clinical Oncology
2016; 12 (1): 6-10
Abstract
Metastatic breast cancer is generally considered incurable, and this colors doctor-patient interactions for patients with metastatic disease. Although true for most patients, there appear to be important exceptions, instances where long-term disease-free survival occurs. Although these instances are few in number, they suggest the possibility of cure. How will we move toward cure for a much larger population of patients with metastatic disease? This article outlines a potential research agenda that might move us toward that distant goal.
View details for DOI 10.1200/JOP.2015.008953
View details for PubMedID 26759458
-
Collective Wisdom: Lobular Carcinoma of the Breast.
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting
2016; 35: 18-21
View details for DOI 10.14694/EDBK_100002
View details for PubMedID 27249682
-
Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: a trial of the ECOG-ACRIN cancer research group (E2198)
BRITISH JOURNAL OF CANCER
2015; 113 (12): 1651-1657
Abstract
Blockade of human epidermal growth factor receptor type 2 (HER2) has dramatically improved outcome for patients with HER2-positive breast cancer. Trastuzumab, an anti-HER2 monoclonal antibody, has previously demonstrated improvement in overall survival (OS) in patients with metastatic and early stage HER2-positive breast cancer. However, trastuzumab can cause congestive heart failure (CHF) with an increased frequency for patients who have also received an anthracycline. The current trial was designed to evaluate the impact of the duration of trastuzumab on CHF.E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer. The patients were randomised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide (abbreviated Arm) or the aforementioned treatment with additional 1 year of trastuzumab (conventional Arm). The primary end point was to evaluate the safety of this variable duration of trastuzumab therapy, particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease >10%. Secondary end points included disease-free survival (DFS) and OS.Compared with 12-week treatment with trastuzumab, 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity: three patients on the abbreviated Arm and four on the conventional Arm experienced CHF. The 5-year DFS was 76% and 73% for the abbreviated and conventional Arms, respectively, with a hazard ratio (HR) of 1.3 (95% CI: 0.8-2.1; P=0.3). There was also no statistically significance difference in OS (HR, 1.4; P=0.3).Compared with 12 weeks of treatment, 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity. Although not powered for efficacy comparisons, the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority.
View details for DOI 10.1038/bjc.2015.405
View details for Web of Science ID 000368449500002
View details for PubMedCentralID PMC4701997
-
Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: a trial of the ECOG-ACRIN cancer research group (E2198).
British journal of cancer
2015; 113 (12): 1651-7
Abstract
Blockade of human epidermal growth factor receptor type 2 (HER2) has dramatically improved outcome for patients with HER2-positive breast cancer. Trastuzumab, an anti-HER2 monoclonal antibody, has previously demonstrated improvement in overall survival (OS) in patients with metastatic and early stage HER2-positive breast cancer. However, trastuzumab can cause congestive heart failure (CHF) with an increased frequency for patients who have also received an anthracycline. The current trial was designed to evaluate the impact of the duration of trastuzumab on CHF.E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer. The patients were randomised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide (abbreviated Arm) or the aforementioned treatment with additional 1 year of trastuzumab (conventional Arm). The primary end point was to evaluate the safety of this variable duration of trastuzumab therapy, particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease >10%. Secondary end points included disease-free survival (DFS) and OS.Compared with 12-week treatment with trastuzumab, 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity: three patients on the abbreviated Arm and four on the conventional Arm experienced CHF. The 5-year DFS was 76% and 73% for the abbreviated and conventional Arms, respectively, with a hazard ratio (HR) of 1.3 (95% CI: 0.8-2.1; P=0.3). There was also no statistically significance difference in OS (HR, 1.4; P=0.3).Compared with 12 weeks of treatment, 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity. Although not powered for efficacy comparisons, the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority.
View details for DOI 10.1038/bjc.2015.405
View details for PubMedID 26625004
View details for PubMedCentralID PMC4701997
-
Prospective Validation of a 21-Gene Expression Assay in Breast Cancer
NEW ENGLAND JOURNAL OF MEDICINE
2015; 373 (21): 2005-2014
Abstract
Prior studies with the use of a prospective-retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker.We performed a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence).Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6).Among patients with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).
View details for DOI 10.1056/NEJMoa1510764
View details for Web of Science ID 000364957700006
View details for PubMedID 26412349
View details for PubMedCentralID PMC4701034
-
Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199
CLINICAL CANCER RESEARCH
2015; 21 (22): 5082-5091
Abstract
Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN.We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199.When evaluating for grade 3-4 TIPN, 120 SNPs had a P value of <10(-4) from patients of European descent (EA) in ECOG-5103. Thirty candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with grade 3-4 TIPN (P = 1.7 × 10(-3); OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2-4 TIPN (HR, 2.1; P = 5.6 × 10(-16)) and grade 3-4 TIPN (HR, 2.6; P = 1.1 × 10(-11)) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2-4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10(-7)).rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.
View details for DOI 10.1158/1078-0432.CCR-15-0586
View details for Web of Science ID 000364488700016
View details for PubMedID 26138065
View details for PubMedCentralID PMC4717479
-
IS A TWO-SPEED (RICH VS POOR) ONCOLOGY INEVITABLE?
CHURCHILL LIVINGSTONE. 2015: S34
View details for DOI 10.1016/S0960-9776(15)30048-5
View details for Web of Science ID 000365078900036
-
A Call for Viewpoints.
JAMA oncology
2015; 1 (4): 432-?
View details for DOI 10.1001/jamaoncol.2015.1238
View details for PubMedID 26181249
-
Targeted Therapy for Cancer in the Genomic Era.
Cancer journal
2015; 21 (4): 294-298
Abstract
The advent of cancer genomics has led to the development of many highly successful targeted therapies, primarily inhibitors of growth factor receptors and related kinases, including imatinib for chronic myeloid leukemia and trastuzumab for HER2-positive breast cancer. This approach has become highly successful for certain cancers. However, as the list of targeted therapies expands, their efficacy becomes more limited, and toxicity accumulates. What we have learned in the past decades is that while the targeted therapeutics approach may be highly successful in less complex tumors, cancers defined by carcinogen-induced genomic chaos, such a UV-induced melanoma or tobacco-induced lung cancer, are driven by a multitude of competing molecular pathways and, as such, are not as successfully managed by a similar approach. Luckily, in the past years, the field of cancer immunotherapy has become more fully developed with the emergence of checkpoint blockade inhibitor therapy. These promising new agents are particularly well suited for tumors with a high mutational burden due to underlying genomic disarray. While still in its infancy, we predict that cancer immunotherapy will offer a better alternative to our current targeted approach and eagerly await the results of several ongoing clinical trials that will elucidate this new direction in cancer therapy.
View details for DOI 10.1097/PPO.0000000000000135
View details for PubMedID 26222081
-
"Vertical" Inhibition of HER2 Yields Horizontal Gains in the Clinic.
Clinical cancer research
2015; 21 (12): 2663-2665
Abstract
HER2-targeted therapy has moved beyond trastuzumab to include other monoclonals targeting the cell surface, receptor tyrosine kinase inhibitors of HER2, and antibody-drug conjugates. Afatinib, a small molecule receptor tyrosine kinase inhibitor, now joins the ranks of HER2-targeting agents in combination with trastuzumab. The combination brings new opportunities and challenges.
View details for DOI 10.1158/1078-0432.CCR-14-3183
View details for PubMedID 26078429
-
Effect of Unblinding on Participants' Perceptions of Risk and Confidence in a Large Double-blind Clinical Trial of Chemotherapy for Breast Cancer
JAMA ONCOLOGY
2015; 1 (3): 369-374
Abstract
Blinding patients to treatment regimen is an important component of high-quality randomized clinical trials, although concern exists about how receipt of a placebo will affect participants' views, particularly among patients with cancer.To determine whether unblinding of random assignment to placebo vs experimental agent in a large adjuvant breast cancer chemotherapy randomized clinical trial was associated with perception of greater chance of cancer recurrence and lower confidence in the decision to participate in the trial in participants who were randomized to placebo compared with those randomized to experimental therapy.Serial telephone-based prospective survey substudy of all Eastern Cooperative Oncology Group Protocol 5103 (ECOG5103) participants enrolling between January 5 and June 8, 2010. In ECOG5103, patients were randomized to receive standard adjuvant chemotherapy for breast cancer with either placebo or bevacizumab for either approximately 6 or approximately 12 months. Treatment assignment was unblinded by 24 weeks, and then patients were surveyed.Trial participants' self-reported perceived risk of recurrence and confidence in study participation.Of 571 patients in this substudy who started protocol therapy, 550 were still in the study at unblinding and 492 (89%) responded to the unblinding survey. At unblinding, 336 of 477 (70%) believed that they had at most a small risk of breast cancer recurrence, and 342 of 480 (71%) reported perceiving at most a small risk of serious problem with therapy; most reported feeling very informed (421 of 483 [87%]) and having high levels of confidence in their study participation (420 of 483 [87%]). The 102 participants who learned that they had been randomized to placebo did not have greater perception of chance of recurrence (P = .48) or fear of recurrence (P = .69), feel less informed (P = .86), or have lower confidence in trial participation (P = .31) compared with the 390 participants who had been randomized to experimental therapy. Patients who learned that they had been randomized to bevacizumab perceived higher risk of having a serious problem caused by treatment (P = .01).In a placebo-controlled, double-blind randomized clinical trial of chemotherapy for breast cancer, unblinding to randomization allocation did not significantly affect most participants' views except for chance of a serious problem from experimental treatment, regardless of receipt of placebo or experimental anticancer therapy along with standard chemotherapy.
View details for DOI 10.1001/jamaoncol.2015.0246
View details for Web of Science ID 000383669100023
View details for PubMedID 26114161
View details for PubMedCentralID PMC4477538
-
Recurrence score and clinicopathologic characteristics of TAILORx participants by race and ethnicity.
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036901140
-
Lymphopenia after adjuvant radiotherapy (RT) to predict poor survival in triple-negative breast cancer (TNBC).
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036900228
-
Everything old is neu again: cellular senescence in HER2-positive breast cancer.
Journal of the National Cancer Institute
2015; 107 (5)
View details for DOI 10.1093/jnci/djv091
View details for PubMedID 25972602
-
A phase III study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive (HR plus ), human epidermal growth factor receptor 2 negative (HER2-) breast cancer (MONARCH 2)
AMER ASSOC CANCER RESEARCH. 2015
View details for DOI 10.1158/1538-7445.SABCS14-OT1-1-07
View details for Web of Science ID 000356730200082
-
Ten year update of E1199: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer
AMER ASSOC CANCER RESEARCH. 2015
View details for DOI 10.1158/1538-7445.SABCS14-S3-03
View details for Web of Science ID 000356730200020
-
Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial.
Journal of clinical oncology
2015; 33 (7): 701-708
Abstract
To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer.DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme.Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P < .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64).Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.
View details for DOI 10.1200/JCO.2014.57.6298
View details for PubMedID 25605861
View details for PubMedCentralID PMC4334774
-
Genomic Analysis Reveals That Immune Function Genes Are Strongly Linked to Clinical Outcome in the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial
JOURNAL OF CLINICAL ONCOLOGY
2015; 33 (7)
Abstract
To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer.DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme.Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P < .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64).Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.
View details for DOI 10.1200/JCO.2014.57.6298
View details for Web of Science ID 000352524200009
View details for PubMedID 25605861
View details for PubMedCentralID PMC4334774
-
Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients
JOURNAL OF NEURO-ONCOLOGY
2015; 122 (1): 205-216
Abstract
The overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4-22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5-25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4-10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0-100.0; p = 0.008). A profile including 13 genes was associated with early (≤36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6-16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer.
View details for DOI 10.1007/s11060-014-1704-y
View details for Web of Science ID 000351091500023
View details for PubMedID 25559688
View details for PubMedCentralID PMC4353882
-
The future of breast cancer systemic therapy: the next 10 years.
Journal of molecular medicine (Berlin, Germany)
2015; 93 (2): 119-125
Abstract
Over the past 50 years, substantial progress has been made in the systemic treatment of early-stage and advanced breast cancer. The use of chemotherapy in the adjuvant and metastatic settings has demonstrated proven efficacy and it has been clearly demonstrated that targeting the estrogen receptor and human growth factor receptor 2 (HER2) is efficacious in early and advanced disease. Despite these advances, vexing clinical challenges remain particularly related to the treatment of triple-negative breast cancer (TNBC; estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) where little progress has been made therapeutically in more than a decade. While recurrences of hormone-responsive breast cancer are overall less common, late relapses after cessation of endocrine therapy are a more frequent occurrence in modern times and reflect the problem of underlying tumor dormancy that as yet has not been overcome. Multiple molecular tools are now available to interrogate the biology of breast cancer, though exactly how to make this information meaningful in the clinic has proven challenging, and molecularly driven clinical trials have faced feasibility challenges. In parallel, focus has expanded from tumor to host with the ability to ascertain underlying germline alterations, such as inherited BRCA1 and BRCA2 mutations, which may be responsible for breast cancer carcinogenesis and, importantly, may have implications for treatment. These clinical advances in germline genetics, made possible by both scientific investigation as well as the courts, still face challenges related to increasing encounters with variants of unknown significance and difficulty in predicting risks associated with less well-characterized inherited cancer predisposition syndromes. In this paper, we attempt to predict the next 10 years of breast cancer, in particular focusing on how the past serves as prologue to the future in this disease.
View details for DOI 10.1007/s00109-014-1238-y
View details for PubMedID 25566982
-
Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial.
Journal of clinical oncology
2015; 33 (3): 265-271
Abstract
Treatment-emergent symptoms with adjuvant tamoxifen and aromatase inhibitors (AIs) have been associated with superior recurrence-free survival (RFS). We hypothesized that MA.27 anastrozole- or exemestane-treated patients with new or worsening vasomotor and/or joint symptoms would have improved RFS.MA.27 randomly assigned 7,576 postmenopausal women with breast cancer to 5 years of anastrozole or exemestane. Patient-reported symptoms were collected using the Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month clinical visits. Symptoms were considered present with either vasomotor and/or joint complaints. Associations between symptoms and baseline patient characteristics were examined with χ(2) and Fisher's exact tests. Subsequent effects of new or worsening symptoms on RFS were examined with landmark analyses and stratified univariable and multivariable Cox models. We examined the effects of 3-month symptoms arising from unplanned clinic visits as a result of severe toxicity.Patients were assessable if eligible for the MA.27 trial, received some trial therapy, and had no disease recurrence at the end of a symptom assessment period; 96% of patients (n = 7,306 patients) were included at 6 months, and 96% (n = 7,246) were included at 12 months. Thirty-four percent of patients had baseline symptoms. For patients without baseline symptoms, 25% and 52% had new symptoms by 6 and 12 months, respectively. Neither treatment-emergent nor baseline symptoms significantly impacted RFS (P > .10) in patients with or without baseline symptoms.In MA.27, anastrozole or exemestane treatment-emergent symptoms were not associated with improved RFS. Women should be supported through treatment and encouraged to remain on their AI regardless of their symptoms.
View details for DOI 10.1200/JCO.2014.57.6926
View details for PubMedID 25512454
View details for PubMedCentralID PMC4289722
-
Treatment-Associated Musculoskeletal and Vasomotor Symptoms and Relapse-Free Survival in the NCIC CTG MA.27 Adjuvant Breast Cancer Aromatase Inhibitor Trial
JOURNAL OF CLINICAL ONCOLOGY
2015; 33 (3): 265-U163
Abstract
Treatment-emergent symptoms with adjuvant tamoxifen and aromatase inhibitors (AIs) have been associated with superior recurrence-free survival (RFS). We hypothesized that MA.27 anastrozole- or exemestane-treated patients with new or worsening vasomotor and/or joint symptoms would have improved RFS.MA.27 randomly assigned 7,576 postmenopausal women with breast cancer to 5 years of anastrozole or exemestane. Patient-reported symptoms were collected using the Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month clinical visits. Symptoms were considered present with either vasomotor and/or joint complaints. Associations between symptoms and baseline patient characteristics were examined with χ(2) and Fisher's exact tests. Subsequent effects of new or worsening symptoms on RFS were examined with landmark analyses and stratified univariable and multivariable Cox models. We examined the effects of 3-month symptoms arising from unplanned clinic visits as a result of severe toxicity.Patients were assessable if eligible for the MA.27 trial, received some trial therapy, and had no disease recurrence at the end of a symptom assessment period; 96% of patients (n = 7,306 patients) were included at 6 months, and 96% (n = 7,246) were included at 12 months. Thirty-four percent of patients had baseline symptoms. For patients without baseline symptoms, 25% and 52% had new symptoms by 6 and 12 months, respectively. Neither treatment-emergent nor baseline symptoms significantly impacted RFS (P > .10) in patients with or without baseline symptoms.In MA.27, anastrozole or exemestane treatment-emergent symptoms were not associated with improved RFS. Women should be supported through treatment and encouraged to remain on their AI regardless of their symptoms.
View details for DOI 10.1200/JCO.2014.57.6926
View details for Web of Science ID 000352421400011
View details for PubMedID 25512454
View details for PubMedCentralID PMC4289722
-
Anti-vascular endothelial growth factor therapy in breast cancer: game over?
Journal of clinical oncology
2015; 33 (2): 133-135
View details for DOI 10.1200/JCO.2014.58.1298
View details for PubMedID 25349299
-
Trastuzumab Plus Adjuvant Chemotherapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Planned Joint Analysis of Overall Survival From NSABP B-31 and NCCTG N9831
JOURNAL OF CLINICAL ONCOLOGY
2014; 32 (33): 3744-?
Abstract
Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point.In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed.Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent.The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.
View details for DOI 10.1200/JCO.2014.55.5730
View details for Web of Science ID 000344861400010
View details for PubMedCentralID PMC4226805
-
Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.
Journal of clinical oncology
2014; 32 (33): 3744-3752
Abstract
Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point.In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed.Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent.The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.
View details for DOI 10.1200/JCO.2014.55.5730
View details for PubMedID 25332249
-
Decade in review-targeted therapy: successes, toxicities and challenges in solid tumours.
Nature reviews. Clinical oncology
2014; 11 (11): 627-628
View details for DOI 10.1038/nrclinonc.2014.171
View details for PubMedID 25286974
-
Recurrence score and clinicopathologic characteristics of TAILORx participants by race and ethnicity
AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.26_suppl.36
View details for Web of Science ID 000358246700037
-
Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100
BRITISH JOURNAL OF CANCER
2014; 111 (6): 1241-1248
Abstract
Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension.A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100.When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4).A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.
View details for DOI 10.1038/bjc.2014.430
View details for Web of Science ID 000341910900025
View details for PubMedCentralID PMC4453857
-
Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100.
British journal of cancer
2014; 111 (6): 1241-1248
Abstract
Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension.A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100.When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4).A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.
View details for DOI 10.1038/bjc.2014.430
View details for PubMedID 25117820
-
Heterogeneity and Cancer
ONCOLOGY-NEW YORK
2014; 28 (9): 772-778
Abstract
Cancer heterogeneity, long recognized as an important clinical determinant of patient outcomes, was poorly understood at a molecular level. Genomic studies have significantly improved our understanding of heterogeneity, and have pointed to ways in which heterogeneity might be understood and defeated for therapeutic effect. Recent studies have evaluated intratumoral heterogeneity within the primary tumor, as well as heterogeneity observed between primary and metastasis. The existence of clonal heterogeneity in the primary and metastasis also affects response to therapy, since the Darwinian pressures of systemic therapy result in clonal selection for initially rare variants. Novel technologies (such as measurements of circulating tumor cells and circulating tumor DNA) may allow physicians to monitor the emergence of clonal subtypes and intervene at an early point to improve patient prognosis.
View details for Web of Science ID 000342553000006
-
Improving the quality of cancer care in America through health information technology.
Journal of the American Medical Informatics Association
2014; 21 (5): 772-775
Abstract
A recent report from the Institute of Medicine titled Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis, identifies improvement in information technology (IT) as essential to improving the quality of cancer care in America. The report calls for implementation of a learning healthcare IT system: a system that supports patient-clinician interactions by providing patients and clinicians with the information and tools necessary to make well informed medical decisions and to support quality measurement and improvement. While some elements needed for a learning healthcare system are already in place for cancer, they are incompletely implemented, have functional deficiencies, and are not integrated in a way that creates a true learning healthcare system. To achieve the goal of a learning cancer care delivery system, clinicians, professional organizations, government, and the IT industry will have to partner, develop, and incentivize participation.
View details for DOI 10.1136/amiajnl-2013-002346
View details for PubMedID 24352553
View details for PubMedCentralID PMC4147622
-
Past, Present, and Future Challenges in Breast Cancer Treatment
JOURNAL OF CLINICAL ONCOLOGY
2014; 32 (19): 1979-1986
View details for DOI 10.1200/JCO.2014.55.4139
View details for Web of Science ID 000337925500002
-
DNA double-strand break repair genes and oxidative damage in brain metastasis of breast cancer.
Journal of the National Cancer Institute
2014; 106 (7)
Abstract
Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood.Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis-specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group).Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression.BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species-mediated genotoxic stress in the metastatic brain.
View details for DOI 10.1093/jnci/dju145
View details for PubMedID 24948741
View details for PubMedCentralID PMC4073622
-
Past, present, and future challenges in breast cancer treatment.
Journal of clinical oncology
2014; 32 (19): 1979-1986
View details for DOI 10.1200/JCO.2014.55.4139
View details for PubMedID 24888802
-
Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: Final results from Eastern Cooperative Oncology Group E5103
AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.15_suppl.500
View details for Web of Science ID 000358613202275
-
Association of genomic analysis of immune function genes and clinical outcome in the NCCTG (Alliance) N9831 adjuvant trastuzumab trial.
AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.15_suppl.509
View details for Web of Science ID 000358613202283
-
A phase III randomized trial of niraparib versus physician's choice in previously treated, HER2-negative, germline-BRCA mutated breast cancer patients: Intergroup study EORTC4307-BCG and BIG5-13
AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.15_suppl.tps659
View details for Web of Science ID 000358613201977
-
Biomarker prediction of chemotherapy-related amenorrhea in premenopausal women with breast cancer participating in E5103
BREAST CANCER RESEARCH AND TREATMENT
2014; 144 (3): 591-597
Abstract
This study aimed to investigate whether pre-chemotherapy anti-mullerian hormone (AMH) is a biomarker for chemotherapy-related amenorrhea (CRA) in breast cancer patients. A multicenter randomized controlled trial, ECOG5103, assigned patients with early stage breast cancer to standard doxorubicin-cyclophosphamide followed by paclitaxel with either placebo or one of two durations of bevacizumab therapy. Five hundred ninety-one patients were part of the decision-making/quality of life substudy, in which there were surveys from baseline through 18-month follow-up. One hundred twenty-four women were included in this analysis of menses data because they were premenopausal at enrollment, responded to the 12-month survey, had not undergone bilateral oophorectomy or ovarian function suppression before that survey, and had serum banked for research before chemotherapy. One hundred of the 124 also responded to the 18-month survey. Median age was 45 years (range 25-55), and median serum AMH level was 0.11 ng/mL (range 0.01-8.63) prior to treatment. Eighty-two percent had CRA at 12 months, and 81 % at 18 months. In multivariate analyses, older age (p = 0.0003) was the only statistically significant predictor of 12-month CRA, but at 18-months, lower pre-chemotherapy AMH (p = 0.04) and older age (p = 0.008) were both statistically significant predictors of CRA. Race, bevacizumab therapy, and tamoxifen use were not statistically significantly associated with CRA after adjustment for AMH and age. Pre-chemotherapy AMH level is a potential novel biomarker for CRA in premenopausal women with early stage breast cancer. Further research to evaluate the clinical utility of AMH testing is warranted.
View details for DOI 10.1007/s10549-014-2891-0
View details for Web of Science ID 000333360700014
View details for PubMedID 24584876
-
Delivering high-quality cancer care: The critical role of quality measurement
HEALTHCARE-THE JOURNAL OF DELIVERY SCIENCE AND INNOVATION
2014; 2 (1): 53–62
Abstract
In 1999, the Institute of Medicine (IOM) published Ensuring Quality Cancer Care, an influential report that described an ideal cancer care system and issued ten recommendations to address pervasive gaps in the understanding and delivery of quality cancer care. Despite generating much fervor, the report's recommendations-including two recommendations related to quality measurement-remain largely unfulfilled. Amidst continuing concerns regarding increasing costs and questionable quality of care, the IOM charged a new committee with revisiting the 1999 report and with reassessing national cancer care, with a focus on the aging US population. The committee identified high-quality patient-clinician relationships and interactions as central drivers of quality and attributed existing quality gaps, in part, to the nation's inability to measure and improve cancer care delivery in a systematic way. In 2013, the committee published its findings in Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis, which included two recommendations that emphasize coordinated, patient-centered quality measurement and information technology enhancements: Develop a national quality reporting program for cancer care as part of a learning health care system; and,Develop an ethically sound learning health care information technology system for cancer that enables real-time analysis of data from cancer patients in a variety of care settings. These recommendations underscore the need for independent national oversight, public-private collaboration, and substantial funding to create robust, patient-centered quality measurement and learning enterprises to improve the quality, accessibility, and affordability of cancer care in America.
View details for DOI 10.1016/j.hjdsi.2013.11.003
View details for Web of Science ID 000218880000012
View details for PubMedID 24839592
View details for PubMedCentralID PMC4021589
-
Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing
BREAST CANCER RESEARCH AND TREATMENT
2014; 143 (1): 57-68
Abstract
Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.
View details for DOI 10.1007/s10549-013-2780-y
View details for Web of Science ID 000329295500006
View details for PubMedID 24292813
View details for PubMedCentralID PMC3901081
-
Gene Expression Analysis Reveals Distinct Pathways of Resistance to Bevacizumab in Xenograft Models of Human ER-Positive Breast Cancer
JOURNAL OF CANCER
2014; 5 (8): 633-645
View details for DOI 10.7150/jca.8466
View details for Web of Science ID 000345216400003
-
TCGA's Breast Cancer Project May Yield Important Therapeutic Benefits, but It's Too Early to Be Sure
ONCOLOGY-NEW YORK
2013; 27 (12): 1280-+
View details for Web of Science ID 000329012400010
View details for PubMedID 24624546
-
Lessons learned from the development of the CancerLinQ prototype: Clinical decision support.
AMER SOC CLINICAL ONCOLOGY. 2013
View details for DOI 10.1200/jco.2013.31.31_suppl.237
View details for Web of Science ID 000335565500230
-
ADVANCES IN ADVANCED TRIPLE NEGATIVE BREAST CANCER
CHURCHILL LIVINGSTONE. 2013: S19
View details for Web of Science ID 000327909300004
-
Biomarker prediction of chemotherapy-related amenorrhea.
AMER SOC CLINICAL ONCOLOGY. 2013
View details for Web of Science ID 000335419602812
-
Does biomarker information impact patients' preferences for therapy?
AMER SOC CLINICAL ONCOLOGY. 2013
View details for Web of Science ID 000335419602246
-
ASCO's approach to a learning health care system in oncology.
Journal of oncology practice / American Society of Clinical Oncology
2013; 9 (3): 145-148
Abstract
The promise of emerging science and the challenges confronting today's health care system can both be addressed by fully embracing the IoM's vision of a learning health care system. ASCO's initial foray into realizing this vision for oncology shows great promise.
View details for DOI 10.1200/JOP.2013.000957
View details for PubMedID 23942494
View details for PubMedCentralID PMC3651563