Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 1/2017

Open Access 01-12-2017 | Research article

Association of pre-chemotherapy peripheral blood pro-inflammatory and coagulation factors with reduced relative dose intensity in women with breast cancer

Authors: Yuan Yuan, Nilesh Vora, Can-Lan Sun, Daneng Li, Enrique Soto-Perez-de-Celis, Joanne Mortimer, The-hang Luu, George Somlo, James Waisman, David Smith, Joseph Chao, Vani Katheria, Timothy Synold, Vivi Tran, Shu Mi, Abrahm Levi, Anait Arsenyan, Jennifer Choi, Laura Zavala, Susan Yost, Arti Hurria

Published in: Breast Cancer Research | Issue 1/2017

Login to get access

Abstract

Background

Chemotherapy decreases the risk of relapse and mortality in early-stage breast cancer (BC), but it comes with the risk of toxicity. Chemotherapy efficacy depends on relative dose intensity (RDI), and an RDI < 85% is associated with worse overall survival. The pro-inflammatory (interleukin (IL)-6, C-reactive protein (CRP)) and coagulation factors (D-dimer) serve as biomarkers of aging. The purpose of this study is to determine if these biomarkers are associated with reduced RDI in women with stage I–III BC.

Methods

This study enrolled women with stage I–III BC. Prior to adjuvant or neoadjuvant chemotherapy, peripheral blood was collected for biomarker measurement. Dose reductions and delays were captured and utilized to calculate the RDI delivered. Univariate and multivariate analyses were performed to describe the association between pre-chemotherapy IL-6, CRP, and D-dimer levels and an RDI < 85%, controlling for relevant tumor and patient factors (age, stage, receptor status, chemotherapy regimen, and pre-chemotherapy physical function and comorbidity).

Results

A total of 159 patients (mean age 58 years, range 30–81, SD 11.3) with stage I–III BC were enrolled. An RDI < 85% occurred in 22.6% (N = 36) of patients and was associated with higher pre-chemotherapy IL-6 (OR 1.14, 95% CI 1.04–1.25; p = 0.006) and D-dimer (OR 2.32, 95% CI 1.27–4.24; p = 0.006) levels, increased age (p = 0.001), increased number of comorbidities (p = 0.01), and decreased physical function by the Medical Outcomes Survey Activities of Daily Living (ADL) Scale (p = 0.009) in univariate analysis. A multivariate model, including two biomarkers (IL-6 and D-dimer), age, ADL, BC stage, and chemotherapy regimen, demonstrated a significant association between the increased biomarkers and reduced RDI < 85% (OR 2.54; p = 0.04).

Conclusions

Increased pre-chemotherapy biomarkers of aging (IL-6 and D-dimer) are associated with reduced RDI (<85%). Future studies are underway to validate these findings.

Trial registration

ClinicalTrials.gov, NCT01030250. Registered on 3 November 2016.
Appendix
Available only for authorised users
Literature
1.
Shayne M, Crawford J, Dale DC, Culakova E, Lyman GH, Group ANCS. Predictors of reduced dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy. Breast Cancer Res Treat. 2006;100:255–62.CrossRefPubMed
2.
Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332:901–6.CrossRefPubMed
3.
Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994;330:1253–9.CrossRefPubMed
4.
Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood WC, Weiss RB, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer I. 1998;90:1205–11.CrossRef
5.
Piccart MJ, Biganzoli L, Di Leo A. The impact of chemotherapy dose density and dose intensity on breast cancer outcome: what have we learned? Eur J Cancer. 2000;36:S4–10.CrossRefPubMed
6.
Chang J. Chemotherapy dose reduction and delay in clinical practice. evaluating the risk to patient outcome in adjuvant chemotherapy for breast cancer. Eur J Cancer. 2000;36:S11–14.CrossRefPubMed
7.
Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431–9.CrossRefPubMed
8.
9.
Gross CP, McAvay GJ, Guo Z, Tinetti ME. The impact of chronic illnesses on the use and effectiveness of adjuvant chemotherapy for colon cancer. Cancer. 2007;109:2410–9.CrossRefPubMed
10.
Muss HB, Woolf S, Berry D, Cirrincione C, Weiss RB, Budman D, et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA. 2005;293:1073–81.CrossRefPubMed
11.
Sargent DJ, Goldberg RM, Jacobson SD, Macdonald JS, Labianca R, Haller DG, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med. 2001;345(15):1091–7.CrossRefPubMed
12.
Taaffe DR, Harris TB, Ferrucci L, Rowe J, Seeman TE. Cross-sectional and prospective relationships of interleukin-6 and C-reactive protein with physical performance in elderly persons: MacArthur Studies of Successful Aging. J Gerontol A Biol Sci Med Sci. 2000;55:M709–15.CrossRefPubMed
13.
Cesari M, Penninx BWJH, Pahor M, Lauretani F, Corsi AM, Williams GR, et al. Inflammatory markers and physical performance in older persons: The InCHIANTI study. J Gerontol A Biol Sci Med Sci. 2004;59:242–8.CrossRefPubMed
14.
Ferrucci L, Harris TB, Guralnik JM, Tracy RP, Corti MC, Cohen HJ, et al. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc. 1999;47(6):639–46.CrossRefPubMed
15.
Peterson MJ, Thompson DK, Pieper CF, Morey MC, Kraus VB, Kraus WE, et al. A novel analytic technique to measure associations between circulating biomarkers and physical performance across the adult life span. J Gerontol A Biol Sci Med Sci. 2016;7:196–202.CrossRef
16.
Lu Y, Tan C, Nyunt M, Mok E, Camous X, Kared H, et al. Inflammatory and immune markers associated with physical frailty syndrome: findings from Singapore Longitudinal Aging Studies. Oncotarget. 2016;7:28783–95.CrossRefPubMedPubMedCentral
17.
Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506–12.CrossRefPubMed
18.
Stewart AL & Ware, Jr. JE, editors. Measuring functioning and well-being: the medical outcomes study approach. Durham: Duke University Press; 1992.
19.
Fillenbaum GG, Smyer MA. The development, validity, and reliability of the OARS multidimensional functional assessment questionnaire. J Gerontol. 1981;36:428–34.CrossRefPubMed
20.
Karnofsky DA, Burchenal JH. The Clinical evaluation of chemotherapeutic agents in Cancer. In: MacLeod CM, editors. New York: Evaluation of Chemotherapeutic Agents, Columbia University Press; 1949.
21.
Podsiadlo D, Richardson S. The Timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39:142–8.CrossRefPubMed
22.
23.
Pieper CF, Rao KM, Currie MS, Harris TB, Cohen HJ. Age, functional status, and racial differences in plasma D-dimer levels in community-dwelling elderly persons. J Gerontol A Biol Sci Med Sci. 2000;55:M649–57.CrossRefPubMed
24.
Allin KH, Bojesen SE, Nordestgaard BG. Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol. 2009;27:2217–24.CrossRefPubMed
25.
Wilson CJ, Cohen HJ, Pieper CF. Cross-linked fibrin degradation products (D-Dimer), plasma cytokines, and cognitive decline in community-dwelling elderly persons. J Am Geriatr Soc. 2003;51:1374–81.CrossRefPubMed
26.
Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw. 2009;7:99–108.CrossRefPubMed
27.
Yuan JQ, Wang SM, Tang LL, Mao J, Wu YH, Hai J, et al. Relative dose intensity and therapy efficacy in different breast cancer molecular subtypes: a retrospective study of early stage breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat. 2015;151:405–13.CrossRefPubMed
28.
Loibl S, Skacel T, Nekljudova V, Lück HJ, Schwenkglenks M, Brodowicz T, et al. Evaluating the impact of relative total dose intensity (RTDI) on patients’ short and long-term outcome in taxane-and anthracycline-based chemotherapy of metastatic breast cancer − a pooled analysis. BMC Cancer. 2011;11:131.CrossRefPubMedPubMedCentral
29.
Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol. 2003;21:4524–31.CrossRefPubMed
30.
Crivellari D, Bonetti M, Castiglione-Gertsch M, Gelber RD, Rudenstam C-M, Thürlimann B, et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. J Clin Oncol. 2000;18:1412–22.CrossRefPubMed
31.
Dees EC, O'Reilly S, Goodman SN, Sartorius S, Levine MA, Jones RJ, et al. A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest. 2000;18:521–9.CrossRefPubMed
32.
Mayers C, Panzarella T, Tannock IF. Analysis of the prognostic effects of inclusion in a clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma. Cancer. 2001;91:2246–57.CrossRefPubMed
33.
Sandy J, Della‐Fiorentina S. Relative dose intensity in early stage breast cancer chemotherapy: A retrospective analysis of incidence, risk factors and outcomes at a south‐west Sydney cancer clinic. Asia Pac J Clin Oncol. 2013;9:365–72.CrossRefPubMed
34.
Weycker D, Barron R, Edelsberg J, Kartashov A, Lyman GH. Incidence of reduced chemotherapy relative dose intensity among women with early stage breast cancer in US clinical practice. Breast Cancer Res Treat. 2012;133:301–10.CrossRefPubMed
35.
Falandry C, Bonnefoy M, Freyer G, Gilson E. Biology of cancer and aging: a complex association with cellular senescence. J Clin Oncol. 2014;32:2604–10.CrossRefPubMed
36.
Pallis AG, Hatse S, Brouwers B, Pawelec G, Falandry C, Wedding U, et al. Evaluating the physiological reserves of older patients with cancer: the value of potential biomarkers of aging? J Geriatr Oncol. 2014;5:204–18.CrossRefPubMed
37.
Ferrucci L, Cavazzini C, Corsi A, Bartali B, Russo CR, Lauretani F, et al. Biomarkers of frailty in older persons. J Endocrinol Invest. 2002;25:S10–5.CrossRef
38.
Singh T, Newman AB. Inflammatory markers in population studies of aging. Ageing Res Rev. 2011;10:319–29.CrossRefPubMed
39.
Walston J, McBurnie M, Newman A, et al. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. Arch Intern Med. 2002;162:2333–41.CrossRefPubMed
40.
Zhang GJ, Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res. 1999;19:1427–32.PubMed
41.
Blackwell K, Haroon Z, Broadwater G, Berry D, Harris L, Iglehart JD, et al. Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status. J Clin Oncol. 2000;18:600–8.CrossRefPubMed
42.
Sanoff HK, Deal AM, Krishnamurthy J, Torrice C, Dillon P, Sorrentino J, et al. Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer. J Natl Cancer Inst. 2014;106:dju057.CrossRefPubMedPubMedCentral
43.
Brouwers B, Hatse S, Dal Lago L, Neven P, Vuylsteke P, Dalmasso B, et al. The impact of adjuvant chemotherapy in older breast cancer patients on clinical and biological aging parameters. Oncotarget. 2016;7:29977.CrossRefPubMedPubMedCentral
44.
Extermann M, Leeuwenburgh C, Samiian L, Sehovic M, Xu J, Cubitt C, et al. Impact of chemotherapy on medium-term physical function and activity of older breast cancer survivors, and associated biomarkers. J Geriatr Oncol. 2016;8:69–75.CrossRefPubMed
Metadata
Title
Association of pre-chemotherapy peripheral blood pro-inflammatory and coagulation factors with reduced relative dose intensity in women with breast cancer
Authors
Yuan Yuan
Nilesh Vora
Can-Lan Sun
Daneng Li
Enrique Soto-Perez-de-Celis
Joanne Mortimer
The-hang Luu
George Somlo
James Waisman
David Smith
Joseph Chao
Vani Katheria
Timothy Synold
Vivi Tran
Shu Mi
Abrahm Levi
Anait Arsenyan
Jennifer Choi
Laura Zavala
Susan Yost
Arti Hurria
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-017-0895-5

Other articles of this Issue 1/2017

Breast Cancer Research 1/2017 Go to the issue

Research article

Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer

Erratum

Erratum to: Cancer progression by breast tumors with Pit-1-overexpression is blocked by inhibition of metalloproteinase (MMP)-13

Erratum

Erratum to: Loss of plakoglobin promotes decreased cell-cell contact, increased invasion, and breast cancer cell dissemination in vivo

Research article

Overexpression of syndecan-1, MUC-1, and putative stem cell markers in breast cancer leptomeningeal metastasis: a cerebrospinal fluid flow cytometry study

Erratum

Erratum to: Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-кB mediated matrix metalloproteinase-1 gene regulation

Research article

Endocrine therapy initiation, discontinuation and adherence and breast imaging among 21-gene recurrence score assay-eligible women under age 65
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits